Despite a promising opening 20 or so minutes, Argentina was left flat-footed by a stunning Philippe Coutinho opener, which was followed up by talisman Neymar scoring a second and Paulinho adding a third to seal a memorable "superclasico" for the hosts.
The victory was another confidence-booster for Brazil, which suffered a humiliating semifinal loss to Germany two years ago at the same stadium, the Estadio Mineirao in Belo Horizonte, and marked another crucial step toward qualifying for the 2018 finals in Russia.
The defeat leaves Argentina in a perilous position, adrift in sixth place in the qualifying table and a point off the automatic qualification places.
There are seven games to go in the run-up to the next tournament in Russia, but the previous edition's finalist is suffering a terrible run of form.
Brazil maintains its one point lead over Uruguay, while Leo Messi's Argentina face a must-win game against Colombia on Tuesday.
Table remains competitive
At the bottom of the qualifying group, ninth-place Venezuela was similarly rampant, scoring five unanswered goals against last-placed Bolivia, hauling itself off the bottom of the table in the process.
Second-placed Uruguay beat Ecuador 2-1, Peru beat Paraguay 4-1 and Colombia played out a goalless draw with Chile.
One of the most highly anticipated matches in the European qualifying program is also the sport's oldest. England hosts Scotland at Wembley in what is a must-win for Scotland and its beleaguered manager, Gordon Strachan.
A furore over the two teams' decision to wear ceremonial poppies on black armbands -- the flower is a British tradition to mark Armistice Day -- threatens to distract from the on-field battle. FIFA regulations ban any political or religious symbols to be displayed on national team uniforms and the two countries' football associations could potentially face fines for going ahead with the decision.
"It's part of our identity as a nation," England's caretaker manager, Gareth Southgate, told the BBC
. "We're just pleased that we can honor the sacrifice of those who have gone before us."
Elsewhere in Europe, eyes are on Paris where Group A leaders France and Sweden meet two days before the anniversary of last year's terrorist attacks, and surprise Euro 2016 semifinalist Wales hosts Group D joint leaders Serbia in Cardiff. Current world champion Germany faces minnow San Marino.
In African qualifying, the match of the weekend is Nigeria vs. Algeria, with the two teams facing off in Uyo. Elsewhere, Senegal travels to South Africa and Morocco hosts the Ivory Coast in Marrakesh.
Russia, which qualifies for the 2018 World Cup as host, was beaten 2-1 in a friendly against 2022 host Qatar in the Gulf country.