Starting on the bench, the Argentine watched his teammates build a three-goal lead in the first half thanks to a brace from Rafinha and a late Luis Suarez strike.
Manager Luis Enrique introduced Messi 10 minutes into the second half and he took just three minutes to get himself onto the score sheet.
Neymar threaded an intricate through ball into his path and Messi fired into the roof of the net at the near post.
"We knew what the game required," Enrique said after the match. "And the players came out and did what they needed to do."
"They didn't create any scoring chances and we did. That's what we wanted to do and we did it.
"We got Messi back and everyone saw it took him very little time to get back to his best level."
However, it was La Liga's surprise package Sevilla which went top of the table early in the day thanks to a first away win in the league in 512 days, a barren run stretching 17 months.
Pablo Sarabia's late, curling strike gave Jorge Sampaoli's men a two point lead at the summit of La Liga.
How would Real and Atletico Madrid respond? Emphatically, would be the answer.
Despite falling behind to an early Isaac Cuenca goal, Belgium international Yannick Carrasco scored a hat-trick as Atletico hit back to score seven past Granada.
So often reliant on defensive resilience to grind out results, this is now the third time Diego Simeone's new-look attacking side has scored four or more goals in the league this season.
Last season it managed it once.
"I think that we started the match well," Simeone told reporters. "They began by competing well but, undoubtedly, the goal woke us up a bit more.
"We tried to transmit passion and ambition. You can be talented and work it from the structure, but passion and ambition come from within.
"I repeat it again, the best that I see in the group is the response from everyone."
Madrid rival Real ensured it remained level on points with Ateltico at the top of La Liga with a 6-1 hammering of Real Betis and end a run of three straight draws.
Raphael Varane gave the visiting side the lead inside five minutes, before a brace from Isco and goals from Karim Benzema, Marcelo and Cristiano Ronaldo sealed the win.
"The match was a benchmark for us. It's not easy to play like that away from home", Zidane said in his post-match press conference.
"I've got good players, they're intelligent. They knew we had to start strongly and they did that superbly. Playing like that from the first minute makes it difficult for the opponent.
"We worked towards trying to do that and now we have to be consistent and continue in the same way. It's a reference point. It's not easy to play like that away from home."