Having been held to a 1-1 draw by Venezuela last time out, the Albiceleste – who remained top of the CONMEBOL qualification group – took out their frustrations on Oscar Villegas' visitors.
Messi latched onto Lautaro Martinez's pass before coolly dispatching his finish past the oncoming Guillermo Viscarra for a 19th-minute opener, then a quickfire double on the stroke of half-time took the game away from Bolivia.
Messi unselfishly squared for Martinez to tap home their second in the 43rd minute, then recorded his second assist by finding Julian Alvarez with a quick free-kick three minutes into stoppage time, with the Atletico Madrid forward finishing on the bounce at the far post.
Nicolas Otamendi had a potential fourth disallowed for offside shortly after the restart, but they extended their lead further in the 69th minute, substitute Thiago Almada sweeping Nahuel Molina's cutback home.
From there, it was all about Messi, who scored twice in two minutes to bring up his 10th international hat-trick. The Inter Miami star finished on his right foot to cap a lightning break in the 84th minute, then beat Viscarra at his near post from 20 yards out to cap the victory with four minutes remaining.
Data Debrief: Messi ties Ronaldo on historic night for Argentina
Messi's treble took him joint-top of the charts for all-time hat-tricks in international football, alongside Ronaldo.
It was also the first time any player had recorded four or more goal involvements in a CONMEBOL World Cup qualifier since 2011, when Messi's club-mate Luis Suarez scored four times against Chile.
The win, Argentina's biggest in any World Cup qualifier, keeps them three points clear of Colombia at the top of the standings, with 10 of 18 games played. Bolivia sit seventh, 10 points back.
In a letter sent to FIFA on Wednesday, CONMEBOL asked for its opening qualifiers, scheduled for March 26, 27 and 31, to be postponed.
COVID-19 has killed more than 4,600 people worldwide while affecting more than 126,000.
CONMEBOL cited the possibility of players not being able to travel from Europe due to coronavirus as a reason for its request.
"The member countries of CONMEBOL – Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Paraguay, Peru, Uruguay and Venezuela have requested the CONMEBOL to submit to FIFA's consideration the request to postpone the start of the qualifiers for the Qatar 2022 World Cup," the statement read in part.
Lionel Messi's Argentina are due to begin their qualifying campaign against Ecuador in Buenos Aires, while Brazil are scheduled to face Bolivia in Recife.
The other matchday one games are Paraguay-Peru, Uruguay-Chile and Colombia-Venezuela.
Messi scored a hat-trick and provided assists for fellow forwards Lautaro Martinez and Julian Alvarez as the world champions bounced back from a 1-1 draw with Venezuela in style.
The treble – his 10th in international football – took him level with Cristiano Ronaldo at the top of the all-time charts, while he is the first player to register at least four goal involvements in a CONMEBOL World Cup qualifier since Luis Suarez in 2011 (four goals versus Chile).
Messi has refused to give any indication of whether he plans to play at the 2026 World Cup in the past, and for now, he is just enjoying his role in Lionel Scaloni's team.
"It is very nice to play here feeling the affection of the Argentina fans," Messi said after the win.
"It makes me emotional to listen to how they shout my name. We all enjoy this connection with the fans and we love playing at home."
Asked if he would continue for the remainder of this World Cup cycle, he said: "I didn't set any date or deadline about my future.
"I'm just enjoying all this. I am more emotional than ever and taking all the love from the people because I know these could be my last games.
"It's a joy to be present and appreciate this moment. Being surrounded by younger team-mates, given my age, makes me feel like a kid again.
"I find myself doing silly things because I feel so comfortable. As long as I maintain that feeling and can continue contributing to the team, I plan to be here enjoying it."
Argentina face Paraguay and Peru in their next set of qualifiers in November and already have a 10-point cushion to those outside the automatic qualification places.
