It was the first time Kyrgios had played on clay since his infamous meltdown at the Rome Masters in 2019, where he threw a chair across the court and walked off, handing Casper Ruud a win by default.
After a meandering first set, the Australian world number 94 sparked into life when he saved the first of two break points with a second serve ace in the third game of the second. From there, Kyrgios opened up his shoulders and became more assertive from the baseline, as well as serving 18 aces in the closing two sets.
While again admitting clay is not his favourite surface, the 26-year-old was nevertheless pleased by the manner of the win against McDonald.
"He [McDonald] beat me in Washington where I used to play pretty well, and he's a tricky one because he doesn't make too many errors, and clay's obviously not my preferred surface," he said post-match.
"I just served really well, and just started playing more aggressive and found another gear. I would slip and slide a little bit, but my game actually suits the clay quite well."
While US seventh seed Tommy Paul secured a walkover 6-7 (4-6) 7-6 (7-5) 3-2 win against Peter Gojowczyk, Chilean fifth seed and defending champion Cristian Garin also came from a set down to beat Jack Sock 4-6 6-3 7-5.
American sixth seed Frances Tiafoe faced relatively simpler work, defeating unseeded countryman Marcos Giron in straight sets 6-4 6-4.
Two all-American matches also opened play in Houston on Tuesday, with JJ Wolf securing a 6-4 6-4 win over eighth seed Jenson Brooksby in the first, and Steve Johnson defeating Denis Kudla 6-3 4-6 6-4.
Before Tuesday's victory over Mackenzie McDonald, Kyrgios had not played on clay since his infamous meltdown against Casper Ruud at the Rome Masters in 2019, where he threw a chair across the court and walked off during a change of ends.
The 26-year-old Australian wild card's serve kept him in relative control, saving all six break points he faced in the 70-minute match, as well as serving 10 aces and winning 88 per cent of points on his first serve.
"I had to be locked in today and I knew that I had to serve well," Kyrgios said post-match. "It's probably one of the better matches I've played on clay in my career, so I'm pretty happy with the way I came out here today, just put my head down and went to work.
"I've been serving really well, so I just wanted to keep to good habits."
The world number 94 will now face Michael Mmoh, who defeated Sam Querrey 6-2 6-4.
Meanwhile, third seed Reilly Opelka did it relatively tougher in the other all-American clash on Wednesday, coming back from a set down to defeat Mitchell Kreuger 3-6 6-2 6-4.
Opelka came into the match having lost just 13 service games in 19 matches this season, but was broken twice in the opening set against Krueger. The world number 18 has been dealing with a right shoulder injury that forced him to retire at the Miami Open against Francisco Cerundolo.
The 24-year-old still managed 15 aces for the match, including a big serve out wide in the Ad court on match point.
"He played well, I think he came out swinging," Opelka said afterwards. "I think he was free, I wasn't. It's a different situation.
"It was a good opportunity for him to play free and get a win and I'm a guy who hasn't always been the most consistent, especially changing surfaces, so I think it was a good win."
He will face Gijs Brouwer, who progressed past J.J. Wolf with a 6-1 6-1 win.
It was the third day in a row that has been washed out due to persistent rain, but after completing their first set on Wednesday, and their second set on Thursday, Max Purcell was allowed to finish off his 6-4 3-6 6-3 win over Daniel Altmaier.
It was the final first-round matchup yet to conclude, although there is still a second round, quarter-finals, semi-finals and the final to schedule in limited time before the ATP Tour rolls on.
The tournament's top seed, Frances Tiafoe, is yet to play a match yet after receiving a first-round bye, and it is the same case for second seed Tommy Paul.
In a statement, tournament director Bronwyn Greer said: "We want to ensure that our courts are in the best possible condition to complete our tournament this weekend, and with that in mind we have decided to forgo play today with the exception of that first-round match that is deep into the third set."
It is the second day in a row without a match being completed after Wednesday's play only made it through one set.
Max Purcell took the first set of his match against Daniel Altmaier on Wednesday, before Altmaier came back to win the second set on Thursday, and they will hope to complete the match on Friday when they resume with Purcell leading 6-4 3-6 4-3.
John Isner will likely have a do-or-die tie-breaker as soon as his match with Gijs Brouwer resumes, as he trails 6-4 5-6 with the Dutch competitor on serve.
The only other match underway is locked at 4-4 between Denis Kudla and J.J. Wolf.
The giant American, who measures in at six-foot-11, was terrific in the opening set, winning 84 per cent of his successful first serves (16-19) and allowing no break point opportunities.
The second set was much more competitive, as Brouwer broke first to go up 3-1, but Opelka answered instantly and then grabbed the match-winning break when 6-5 up to avoid a tie-breaker.
Opelka will face a fresh Nick Kyrgios in the semi-final after the Australian was gifted a walkover win against Michael Mmoh due to injury.
In a clash between two top-five seeds, world number 29 Christian Garin got the better of world number 13 Taylor Fritz 6-2 6-7 (5-7) 6-3.
What made Garin successful in the first and third sets was his return game, winning more than half of his return points in those sets combined (26-51).
Fritz had chances to get back into the game, but Garin saved 11 of 14 break point opportunities, including six of seven in the deciding third set.
Garin will play American John Isner in the semi-final after Isner triumphed in a three-set battle against Frances Tiafoe 6-4 2-6 6-3.
Isner's trademark serve was inconsistent, and abandoned him in a grim second-set performance, winning just 11 of 21 service points on his way to getting broken twice to allow Tiafoe to force the match into a third frame.
In Isner's two successful sets, he won more than 80 per cent of his first serves (35-41), and allowed no break point opportunities in the third.
In a clash between two of the tour's elite servers, and two of the tallest men to ever play professional tennis, break points were hard to come by, and even harder to convert, as Opelka saved all eight opportunities he faced, while Isner saved four out of five.
That one break decided the first set, as 6ft 10in Isner fought back from 40-0 down to force deuce, but the fourth break point of the game was converted by 6ft 11in rival Opelka.
The ATP said their respective heights made it the tallest tour final in the Open Era.
In a match that was always likely to be decided by whoever served best, Opelka had five aces to Isner's two in the first set, while Isner also had the only double fault.
Isner was much stronger in the second set, creating seven break-point opportunities, but he just could not win the important points as Opelka's serve repeatedly got him out of trouble.
Isner then had three opportunities at set point in the tie-break to force a decider, but it was Opelka's day, as he saved all three and converted his first chance at match point.
After dropping a set in his first-round match against Mitchell Krueger, Opelka was perfect the rest of the tournament, beating Gijs Brouwer and Nick Kyrgios in straight sets on his way to the final.
Persistent rain this week in Houston meant the past three days of play have not been completed forcing a massive pile-up of matches on Saturday with the conditions clearing up.
Tiafoe took on Steve Johnson in the morning, winning 6-2 6-4 in the second round, before toppling Australian sixth seed Jason Kubler 6-4 6-4 in the quarter-finals.
The American, who only had a break of two and a half hours between his two matches, said: "I haven’t played two matches in one day in a long time.
"I thought it was unbelievable how I was able to come out here and play so well."
Tiafoe will take on Dutchman Gijs Brouwer in the last four after he got past fourth seed John Isner 6-4 7-6 (7-4), before taking down fifth seed J.J. Wolf 6-3 6-4.
Second seed Tommy Paul was another fancied American to bow out on Saturday, losing 7-6 (8-6) 6-2 to German qualifier Yannick Hanfmann in the second round.
Hanfmann progressed to the semi-finals where he will face Argentinian eighth seed Tomas Martin Etcheverry, with the German getting past Czech qualifier Tomas Machac 6-2 6-1.
Machac had bundled out American seventh seed Marcos Giron 6-4 6-4 in the second round.
Etcheverry progressed with victories over Australia's Max Purcell and Chile's Cristian Garin, winning the latter 6-1 6-7 (2-7) 6-3 in more than two and a half hours.
