After edging Colombia 2-1 at home on Thursday, Brazil came crashing back to earth against the reigning world champions, who started Tuesday's rout in Buenos Aires with a close-range strike by Julian Alvarez four minutes after kick-off.
Even without the injured Lionel Messi and Lautaro Martinez, Argentina were streets ahead of their rivals and they did not have to wait long to extend their lead.
Enzo Fernandez made it 2-0 with a strike from inside the box in the 12th minute but Brazil pulled one back when a mistake by Argentina defender Cristian Romero gifted Matheus Cunha a goal in the 26th minute.
Argentina restored their two-goal lead through Alexis Mac Allister in the 37th minute, firing home from a Fernandez cross.
Argentina squandered several chances to extend their lead further before substitute Giuliano Simeone wrapped up the scoring with a close-range strike in the 71st minute.
A 0-0 draw between Uruguay and Bolivia earlier on Tuesday had sealed Argentina's spot at the 2026 World Cup as they became the first South American team to qualify for the tournament in North America.
They top the standings with 31 points from 14 matches, 17 points clear of seventh-placed Bolivia, who currently hold the spot for the international playoffs.
Brazil are fourth on 21 points.
Brazil were missing three regular starters — goalkeeper Alisson, defender Gabriel Magalhães and midfielder Bruno Guimarães — and weren't really competitive from start to finish.
It's the first time Argentina have won both matches against Brazil in a World Cup qualifying tournament. The home victory was also Argentina's first against the Brazilians since qualifying for the 2006 World Cup.
Brazil's worst deficit in South American World Cup qualifying history compounded pressure on coach Dorival Júnior, who took over in January of last year.
"All of us can do better than this. It isn't only about Dorival," Brazil's captain Marquinhos said.
"This is not only the coach's fault, it is the players too. We need to have our heads in the right place. They (Argentina) also had tough times before and they overcame it. We can do it too."
