It was Hamilton's 10th victory of the season, finishing 1.4 seconds ahead of Red Bull's Max Verstappen.
But it could have been a very different outcome for the British driver, who struggled with engine problems and medium tires as he waited for rain that never came.
Hamilton's second win in Sao Paulo was only possible after Force India's backmarker Esteban Ocon clashed with race leader Verstappen on lap 44, causing both cars to spin. At the time, the Red Bull driver led Hamilton by five seconds.
"That (incident) put us back in contention," Hamilton said of his rival's setback. "Max is that go-getter guy and every now and again it bites you. But I am really, really proud here, I don't care about anybody else."
Off the track, the 21-year-old Dutchman later confronted - and pushed - former Formula 3 rival Ocon, who refused to apologize despite the stop-go punishment he was given during the race. The Force India driver finished 15th.
Verstappen managed to stay in the race after the incident and get closer to Hamilton in the final laps, but it wasn't enough for his second consecutive victory.
"I hope I can't find him in the paddock now," Verstappen said of Ocon before he met the Force India driver after the race.
Verstappen was given an unusual punishment for the pushes and insults he aimed at Ocon - he will have to perform two days of public service at the direction of motorsport governing body FIA within six months.
Ferrari's Kimi Raikkonen joined Hamilton and Verstappen on the podium. His teammate Sebastian Vettel, who is second in the overall standings, placed sixth.
Hamilton celebrated his win and his team's fifth title with samba dancers on the podium, as Verstappen left still fuming.
"This is what everyone works for, we really pulled together as a unit this year," Hamilton said. His teammate Valtteri Bottas finished fifth.
Mercedes now has an insurmountable 620 points against Ferrari's 553.
It was Hamilton's 72nd victory in Formula One, a much celebrated one after all the problems he faced during the race.
"We were managing that in the last part of the race, we were losing some power," the British driver said.
In the first part of the race Hamilton kept the advantage he acquired by taking his 10th pole position of the season. Bottas overtook Vettel for second place, and for a moment it seemed Mercedes had the race in the bag already.
Verstappen, the winner of the Mexican GP two weeks ago, started in fifth and quickly overtook the two Ferraris, conquered Bottas on lap 10 and showed he would challenge Hamilton for the win.
After the world champion pitted on lap 19, it appeared Mercedes had made the wrong decision by giving Hamilton fresh tires before his rivals. Verstappen only stopped 16 laps later.
With 31 laps to go, Verstappen successfully challenged Hamilton and started building a lead before clashing with Ocon.
The British driver initially opened a lead of five seconds over Verstappen. But the Dutchman started climbing back on every lap, thanks to Hamilton's engine problems and medium tire deterioration.
The race at Interlagos marked the first time since 1970 there were no Brazilian drivers on the grid. Still, attendance was higher than last year's race when Felipe Massa bid farewell driving a Williams. Race organizers said around 150,000 fans attended over three days, 10,000 more than last year.
Massa, who lost the 2008 title to Hamilton and is now a TV pundit, was sorry for Verstappen, but impressed with Hamilton's luck on Sunday.
"We are both huge fans of Ayrton Senna, who nailed some lucky wins every now and then. Only true champions like Hamilton nail wins like this, when all seems lost," the Brazilian said.
The final race of the season is at Abu Dhabi on Nov. 25.
More AP auto racing: https://apnews.com/tag/apf-AutoRacing and https://twitter.com/AP_Sports
Copyright 2018 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.