The Baggy Greens lost badly in the opening match, being bowled all out for 188 runs, but they cruised to victory at YS Raja Reddy Cricket Stadium on Sunday.
India were bowled out for just 117 runs off 26 balls after being sent out to bat first, with Mitchell Starc (5-53) claiming a five-wicket haul in a truly dominant display from the tourists.
Australia's opening batters Mitchell Marsh (66 not out) and Travis Head (51 not out) remained unbeaten to confirm victory inside four hours.
The sides will reconvene in Chennai on Wednesday for the deciding match.
India had lost only one of their nine ODIs at this venue prior to Sunday, but Shubman Gill was sent packing for a duck off the third ball to set the tone for what was to come.
Returning skipper Rohit Sharma (13) started well with a couple of boundaries, but he did not last much longer and India never found any real rhythm.
Only four players reached double figures, with Virat Kohli (31), Ravindra Jadeja (16) and Axar Patel (29 not out) struggling to cause Australia any real problems.
Starc starred with the ball, responsible for the wickets of Mohammed Siraj (0), KL Rahul (9), Suryakumar Yadav (0), Shubman Gill (0) and Rohit.
India's target of 118 for victory was never going to trouble Australia, and so it proved as the explosive pair of Head and Marsh made light work of the hosts' bowlers.
Head smashed Siraj for four successive boundaries in a 50-run stand with Marsh for the first wicket, with the Aussies sealing an emphatic win in just 11 overs.
Marsh and Head blitz completes the job
The best India could hope for after a rather embarrassing batting effort was prolonging this second ODI for as long as possible for the paying spectators.
Marsh and Head clearly had other ideas as they put up an unbeaten partnership of 121 from 66 balls.
That strike rate of 183.33 is the highest for any opening stand in an ODI in India from a minimum of 10 balls.
Sensational Starc leads the way
Take nothing away from Marsh and Head, but the foundations for this incredible victory were laid by Starc, who got five wickets in an ODI for the ninth time.
The defeat was India's first in 10 ODI matches on home soil, ending what was the second-longest active winning streak of any nation in the format.
Paceman Starc was given the green light to fly back to his homeland to support Healy at the MCG on Sunday when Australia face India.
Australia have lost the series against the Proteas with one match to spare and they will have to do without left-arm quick Starc when they go in search of a consolation win in Potchefstroom on Saturday.
Justin Langer, the Australia head coach, said: "It's a once-in-a-lifetime chance for Mitch to watch Alyssa in a home World Cup final and so we were happy to allow him to return home to support his wife and be part of a fantastic occasion,
"It is something we have been talking about for a while, given Mitch has had a considerable workload in all three formats this summer.
"His heading home a couple of days ahead of the rest of the squad means he will have a chance to refresh ahead of our home and away ODIs and Twenty20 internationals against New Zealand that will wrap up our season.
"We have plenty of fast bowling options with us here in South Africa with Josh Hazlewood, Jhye Richardson and Kane Richardson all sitting out our previous match in Bloemfontein, and Mitch's absence will offer one of them an opportunity to impress in Saturday's match."
Starc, 30, left the squad after the first Twenty20 against India due to a family illness.
But in a huge boost for the hosts, the left-armer will re-join his team-mates, with the first Test against India beginning in Adelaide on Thursday.
"We feel for Mitch at this difficult time and we're happy he has taken time out to spend with his family," Australia head coach Justin Langer said.
"We look forward to welcoming him back into the squad on Monday."
After Australia won the ODI series, India claimed a 2-1 victory in the T20s.
Captain Finch top scored with 63 off 44 balls as the holders posted 179-5 at the Gabba on Monday, with Marcus Stoinis making 35.
Barry McCarthy (3-29) and Josh Little (2-21) were the pick of the Ireland bowler in Brisbane.
Finch was off the field due to a hamstring problem for the run chase, but Ireland were unable to inflict more pain on him as they were all out for 137 after being reduced to 25-5 in a devastating opening four overs that saw Mitchell Starc (2-43) and Glenn Maxwell (2-14) take two wickets apiece.
Maxwell and Starc dismissed Paul Stirling, Harry Tector, Curtis Campher and George Dockrell between them, with Pat Cummins cleaning up Andy Balbirnie.
A superb innings from wicketkeeper-batter Lorcan Tucker (71 not out from 48) salvaged some pride for Ireland, but they were unable to pull off another shock after stunning England last week and are down in fourth place.
The hosts will play Afghanistan in their final Super 12 game at Adelaide Oval on Friday, with group leaders New Zealand and third-placed England meeting in a huge encounter on Tuesday.
Hosts reaffirm credentials
After a humiliating defeat to the Black Caps started their tournament on the wrong foot, Australia look to be back into the swing of things.
There will be concern over Finch’s injury, though, and David Warner missed out again as he fell for only three. Ireland’s rally also prevented Australia from significantly improved their net run-rate.
Tucker tucks in
Tucker demonstrated an array of dazzling shots to frustrate Australia, hitting a six and finding the rope nine times against a top-quality attack.
Though his efforts were ultimately in vain, he blew away the previous best score for an Ireland batter in this format against Australia, exceeding Kevin O'Brien's 35 posted back in 2012.
Australia and the Proteas will lock horns for the first time since the fateful 2018 tour of South Africa in a three-game Test series starting on Saturday at the Gabba in Brisbane.
The 2018 scandal rocked Australian cricket, leading to Steve Smith and David Warner's 12-month bans, along with the loss of their leadership positions. Head coach Darren Lehmann stepped aside, with Justin Langer instilled in the aftermath to restore the team's reputation.
Khawaja was part of the side for the third Test in Cape Town in 2018 when the ball tampering saga emerged but said those ghosts had been banished.
"It honestly hasn't been and I'm being genuine," Khawaja told reporters on Thursday when asked if the sandpaper scandal had been discussed internally. "It's because time heals all wounds.
"The guys have come so far from there, both as individual players, but also as a team.
"Everyone's got so many different things going on in their life from where they were four years ago. That actually gave guys a lot of perspective.
"Australian cricket, both as a whole and as individual as players, we were probably at rock bottom right there."
Starc was also part of that Australian side in Cape Town, but echoed Khawaja's sentiments.
"I think both teams have probably evolved since," Starc said. "It's been an evolution of our group across the formats.
"We're very happy, chilled, relaxed, [in an] enjoyable environment and hopefully it's going to show in our cricket and result in a positive performance in these three Tests."
Faf du Plessis, who was the South Africa captain during the 2018 series, fueled the flames ahead of the series with an extract in his newly released book, accusing Smith of "milking" physical contact with Kagiso Rabada in the first Test of that tour.
The 2018 series was full of intensity, with the Smith-Rabada clash one of many heated incidents leading up to the fateful sandpaper scandal.
"This episode has almost been forgotten against the backdrop of what the series still had up its sleeve, or more accurately, down its trousers," Du Plessis wrote.
"They brushed shoulders during one of KG’s overs but Smith milked it like a football player. We knew that KG was one demerit point away from a suspension."
Then-captain Steve Smith, David Warner and Cameron Bancroft were banned by Cricket Australia after all three were implicated in a plot to alter the condition of the ball with sandpaper during a 322-run defeat to South Africa at Newlands in March 2018.
Bancroft, who was caught on camera rubbing what was initially thought to be yellow sticky tape on the ball, was punished along with Smith and Warner, the latter as vice-captain also part of Australia's "leadership group".
Head coach Darren Lehman was cleared of any wrong-doing at the time and later stepped down, while the bowling attack of Starc, Hazlewood, Cummins and Lyon were also said to be in the dark.
In an interview with The Guardian last weekend, Bancroft was asked whether the bowlers knew what was going on and replied: "Uh … yeah, look, I think, yeah, I think it's pretty probably self-explanatory."
Cricket Australia invited Bancroft to come forward with any further information after it conducted a full investigation at the time.
In a joint statement published on Starc's website, the Australian bowlers stridently denied any wrongdoing and said it was "time to move on".
"We pride ourselves on our honesty. So it’s been disappointing to see that our integrity has been questioned by some journalists and past players in recent days in regard to the Cape Town Test of 2018," the statement read.
"We have already answered questions many times on this issue, but we feel compelled to put the key facts on the record again.
"We did not know a foreign substance was taken onto the field to alter the condition of the ball until we saw the images on the big screen at Newlands."
Umpires Nigel Long and Richard Illingworth inspected the condition of the ball after Bancroft appeared to tamper with it and did not find enough damage to change it – something Starc, Hazlewood, Cummins and Lyon chose to highlight.
The statement added: "None of this excuses what happened on the field that day at Newlands. It was wrong and it should never have happened.
"We've all learned valuable lessons and we'd like to think the public can see a change for the better in terms of the way we play, the way we behave and respect the game. Our commitment to improving as people and players will continue.
"We respectfully request an end to the rumour-mongering and innuendo. It has gone on too long and it is time to move on."
Head, currently ranked as the fourth-best Test batsman in the world, was questionably dropped for the series opener in Nagpur despite an outstanding Australian summer.
He will come back into the side to replace Matt Renshaw after disappointing with two combined runs from his two innings in Nagpur.
Head will bat at number five, slotting in behind Steve Smith and in front of Peter Handscomb.
Meanwhile, fast bowler Scott Boland was replaced by Kuhnemann, leaving captain Pat Cummins as the only quick in the Australian team.
Kuhnemann brings a different aspect to the Australian spin attack as the only left-armer, earning his Test debut after four appearances in the One Day side.
India announced only one change to their team that ran away with a comfortable victory in the series opener, with Shreyas Iyer slotting in at number five in place of Suryakumar Yadav.
Australia XI: D Warner, U Khawaja, S Smith, M Labuschagne, T Head, P Handscomb, A Carey (wk), P Cummins (c), T Murphy, N Lyon, M Kuhnemann.
India XI: KL Rahul, R Sharma (c), C Pujara, V Kohli, S Iyer, S Bharat (wk), A Patel, R Ashwin, R Jadeja, M Shami, M Siraj.
Holders Australia continued their preparations for the T20 World Cup on home soil with another victory in Brisbane on Friday, Warner making 75 off 41 balls and Tim David 42 from just 20 deliveries in their total of 178-7.
The Windies could only muster 147-8 in reply, Starc the pick of the bowlers with 4-20 and Pat Cummins (2-32) taking his 50th Twenty20 International wicket.
Australia will now travel to Perth for the start of a three-match T20I series against England on Sunday, while West Indies will have to come through their first-round group to qualify for a World Cup Super 12 spot.
The excellent Alzarri Joseph (3-21) dismissed Cameron Green in the second over, but Warner and Aaron Finch got Australia up to 45-1 at the end of the powerplay.
Warner raced to his half-century in 30 balls, but was caught and bowled by Odean Smith in the 12th over after captain Finch fell for a scratchy 15.
Glenn Maxwell was run out for only one and Steve Smith (17) was bowled by Joseph, but David cleared the rope three times in a swashbuckling knock to give Australia some impetus before he was trapped lbw by Obed McCoy (2-33).
Kyle Mayers was brilliantly caught and bowled by Starc in the first over of the Windies' run chase, but Johnson Charles and Brandon King steadied the ship with a stand of 50.
Adam Zampa redeemed himself for dropping Charles on two by getting King (23) stumped and Starc returned to see the back of Nicholas Pooran.
An unconvincing knock from Charles (29) was ended by Green as the wickets continued to tumble, Starc doing the bulk of the damage as Akeal Hosein's knock of 25 came with the Windies never really looking like squaring the series.
Warner sets the tone
Opener Warner was outstanding at the top of the order, laying the foundations for a total that proved to be too big for the Windies to chase down.
He demonstrated his great power and sweet timing, striking three sixes and hitting another 10 boundaries as he registered a brilliant 23rd half-century for his country in the shortest format.
Starc fires, Cummins brings up half-century
Australia will be relying on Starc to be firing on all cylinders when they attempt to retain the World Cup and he bowled beautifully in Brisbane, with a mixture of control and variety.
Cummins was more expensive, but the Test captain reached the 50 T20I wickets landmark in his 44th match.
