Messi, who missed two rounds of the competition in October due to a right ankle injury, played from start to finish on Tuesday in front of raucous fans at the Monumental de Nunez Stadium, who chanted his name after he opened the scoring in the 19th minute.
Arch-rivals Brazil, whose coach Dorival Junior was under pressure earlier this month, got some relief with a convincing performance in a 4-0 home win against Peru.
Argentina remain top of the South American standings with 22 points after 10 matches, three points clear of second-place Colombia, who earlier beat Chile 4-0. Uruguay, who had a goalless draw with Ecuador, and Brazil come next with 16 points.
Ecuador and Paraguay follow, with 13 points each, but the Ecuadorians have one more win to take the fifth position.
The top six teams in the region will secure automatic berths in the next World Cup. The seventh-place team, currently Bolivia, will play in an international playoff for a spot in the tournament in 2026.
Two more rounds of South American World Cup qualifying will be played in November.
Messi's first goal came after a mistake by a Bolivian defender, who missed a pass and allowed the 37-year-old Messi to run freely and finish unchallenged in front of goalkeeper Billy Viscarra.
Messi assisted on Lautaro Martínez's goal in the 42th minute and gave a decisive pass once again in added time on a goal by Julian Alvarez.
Messi's final two goals came in the 84th and 86th minutes.
"We enjoyed this, we are happy to be here playing in Argentina," said Messi, who once again refused to say whether he will play in the next World Cup in 2026.
"This could be one of the last (matches in front of the Argentinian crowd)."
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