Setubal conceded twice in the last seven minutes at the Estadio Dragao, while they also had goalkeeper Ricardo Batista sent off in stoppage time as he conceded a penalty.
The victory took second-placed Porto to 31 points in the Portuguese top flight, three behind leaders Benfica, who host Gil Vicente on Sunday.
Porto also opened up a three-point gap on third-placed Vitoria Guimaraes, who will visit Estoril on Saturday, while Setubal lost their fifth straight match to remain 14th, just two points clear of the relegation zone.
The hosts started strongly with Ricardo Quaresma converting a penalty in the 22nd minute after Setubal's Manu pulled Danilo back in the box, while four minutes later Jackson Martinez struck his 11th goal of the campaign, volleying Cristian Tello's cross into the net.
Yacine Brahimi - who started on the bench in the league for the first time this season - wreaked havoc after being introduced in the 88th minute.
Brahimi made it 3-0 within seconds of replacing Quaresma, blasting the ball into the net after Batista could only parry Juan Fernando Quintero's strike.
And in the 92nd minute, Batista again failed to hold a shot from Quintero and Brahimi was again first to the rebound, lifting the ball over Setubal's goalkeeper, who could only upend Porto's Algerian attacker.
Referee Manuel Oliveira pointed to the spot and showed Batista a red card and with Setubal having already used their three substitutes, Zequinha had to stand in goal and he was unable to stop Danilo's penalty.
