Primeira Liga leaders Benfica had claimed a six-point lead over second-placed Porto with their 2-0 triumph last week but Lopetegui's men responded in impressive fashion against Setubal with Yacine Brahimi's late introduction inspiring the rout at the Estadio Do Dragao.
The win took Porto to 31 points, just three behind Benfica, who play on Sunday, and ended a two-game winless run at home in all competitions for Lopetegui's side.
Porto had to come from behind to draw 1-1 with Shakhtar Donetsk in the UEFA Champions League on December 10 before their loss to Benfica.
"We came back to win and made it 4-0 and we can only be satisfied with this result," Lopetegui said after the win over Setubal.
"We showed character, ambition and hope to make beautiful things in the future.
"We have to look at ourselves and make our way by keeping this attitude and this energy, which will surely make us win more."
Brahimi replaced Ricardo Quaresma in the 88th minute and gave the hosts a 3-0 advantage when he converted the rebound after Setubal goalkeeper Ricardo Batista spilled Juan Fernando Quintero's strike.
Brahimi was also central to his side's fourth goal in stoppage time, pouncing on another parry from Batista, who got to the rebound after Porto's Algerian forward and sent him tumbling in the box.
Batista was sent off and Danilo converted from the spot past Zequinha, who had to stand in goal with Setubal having already used three substitutes, as Porto wrapped up a four-goal win.
Quaresma and Jackson Martinez scored Porto's goals in the first half.
While the win made Porto the highest-scoring team in the Primeira Liga this season, Lopetegui was more impressed by another clean sheet - their eighth of the term.
"We were right on the ball movement and created several chances, it seems to me we deserved the victory," the Spanish coach said.
"We made a good first half, in which we scored two goals and even could have done more.
"In the second half, not wrung out very well, but we managed to stay focused defensively and kept our goal clean."
