The Argentine's match-winning double also extended his scoring streak to 14 consecutive games, but it was far from an easy outing against the Andalusian club, who deservedly opened the scoring through Ighalo to end the first half with the lead.
But Barca would hit back in a dominant second half, as Messi tapped home a rebound five minutes after the restart, before clinching the win with a free-kick in the 73rd minute to provisionally extend the Blaugrana's lead at the top of the table to 15 points over second-placed Atletico Madrid.
With one eye firmly on the midweek trip to Italy to face AC Milan, Jordi Roura opted to rest Andres Iniesta, Carles Puyol and Jordi Alba, with Alexis Sanchez, Javier Mascherano and Adriano stepping into the side.
Granada certainly were not fazed by the reputation of their opponents, and threatened themselves when Nolito forced Victor Valdes to save low after getting to the end of Ighalo’s testing cross.
And with 26 minutes on the clock, the pair would combine once again to open the scoring. Nolito this time played the role of provider, taking advantage of Barca’s hesitancy to clear a cross by centering for Ighalo, who stroked home from yards out.
The Catalans, despite dominating the ball, were struggling to break down the opposition defence, but Adriano went close to an instant response when his swerving shot from the corner of the box flew just off target.
Guilherme Siqueira was lucky to escape with a yellow card after a last-man foul on Pedro, and Granada counted their blessings again when Tono denied Messi, who had ghosted in front of a static defence to connect with Thiago Alcantara’s lovely touch.
But Adriano was withdrawn for Alba shortly before the break, and the change coincided with a drop in Barca’s momentum, and it was the home side who made the stronger finish to the half.
However, five minutes into the second half, the Blaugrana were right back into the match. Cesc Fabregas’ shot caught the defence, and Tono, by surprise, and the ball was parried back into the path of Messi, who slotted home his milestone goal.
Granada seemed flat, and lacked much of the thrust that had defined their first half play, but still, Barca, despite creating more and more chances, were not quite able to apply the killer blow.
Pedro was unlucky to see a fizzing long-range drive crack off the inside of the post, before he was correctly called for offside after turning home a low cross from Alves.
But the breakthrough would come with 17 minutes to go, and it was no surprise to see Messi at the fore again, the Argentine this time converting straight from a free kick 25 yards from goal.
Granada finally awoke from their second-half slumber in the last few minutes of the game. Inigo Lopez sent a free header right into the arms of Valdes, who was forced to work a lot harder to parry a shot from Yacine Brahimi into the side netting during stoppage time.
There was even time for Tono to deny Messi a chance for a hat-trick at the death, and by that point, Barca had done just enough to see out the game, and clinch three hard-earned points.