Argentina's Alexis Mac Allister celebrates scoring their third goal. Picture: REUTERS/Agustin Marcarian
Having secured their spot in next year's tournament prior to kick-off as a result of Bolivia's 0-0 draw with Uruguay, a Lionel Messi-less Argentina were in control from the opening whistle.
Messi has an injury to his adductor and was not included in Argentina’s squad for the two latest matches.
Poor defending allowed striker Julian Alvarez to get Argentina on the board in the fourth minute and some slick passing enabled Enzo Fernandez to double the lead eight minutes later.
Brazil pulled one back in the 26th minute via Matheus Cunha, but a third Argentina goal through Liverpool's Alexis Mac Allister just before half-time halted any momentum for the visitors.
Brazil's struggles continued in the second half as Giuliano Simeone picked up Argentina's fourth goal in the 71st minute.
Striker Julián Álvarez said Argentina's big win "is historic because of the rival, the context, what was said, the great match we played and because we are qualified to the World Cup."
“Very humbly we did our work," he said.
The result marked Brazil's worst defeat in South American World Cup qualifying.
Brazil sit in fourth place in the standings with the top six clinching an automatic spot.