It was far from a classic Juventus performance, with the absence of Serie A top scorer Carlos Tevez to injury clearly felt by the visitors, who had goalkeeper Gianluigi Buffon save a second-half penalty.
Tevez's replacement, Pablo Daniel Osvaldo, had two goals ruled out for offside during a tame first half, and Juve looked on the verge of just their second league loss this season when Arturo Vidal was adjudged to have handled in the penalty area with 19 minutes left.
Buffon was Juventus' hero though, as he has been so many times throughout his illustrious career, comfortably saving a weak effort from Napoli loanee Emanuele Calaio.
Pirlo, who was returning from suspension, then stepped up to score a trademark free-kick that left Genoa goalkeeper Mattia Perin with no chance.
Juventus' latest victory sees them move 17 points clear of the second-placed Roma, who host Udinese on Monday.
Juventus – who brought in Giorgio Chiellini after Andrea Barzagli was injured in the warm-up – were not at their fluent best in a first half dominated by Osvaldo's bad luck.
Ex-Juventus forward Giuseppe Sculli fired over in the sixth minute before Osvaldo was denied with his side's first real chance.
Sebastian De Maio's attempted clearance hit Fernando Llorente and fell to the Southampton loanee, who dinked over goalkeeper Perin and then tapped in, only to see the offside flag raised.
That decision appeared to be correct, but Osvaldo could feel harshly done by after his second effort was chalked off, just after Andrea Bertolacci wasted a free header for the hosts.
Paul Pogba created the chance with an excellent back-heel and again Osvaldo chipped Perin, only to have his celebrations cut short by another offside decision, though replays suggested he had been level.
Pogba showed his skill when he robbed Stefano Sturaro in possession and fired wide from 20 yards but it was a frustrating start for the champions, who saw their run of being in front at the break in nine successive matches come to an end.
After the interval, Bertolacci showed great skill to beat Chiellini before thrashing an effort at Buffon, who was relieved to see Marco Motta's rebound go wide.
Juventus then had a half-hearted penalty appeal turned down, after Llorente fired into the arm of Luca Antonelli from close range, just two minutes before Genoa were awarded a spot-kick.
But Buffon was up to the task as substitute Calaio's tame effort to the right was comfortably saved.
And as a dour draw looked likely, Pirlo stepped up to curl a superb 25-yard winner home as Juventus sealed a fifth consecutive league win.
‘Maybe I’ll be signed by Wrexham, who knows? English football would suit me – if an offer came, I wouldn’t think twice, I’d go immediately’ Euro 2024 cult hero reveals his UK dream
‘Managing Leeds? It was an option that appeared, but it wasn’t the right timing. I decided it wasn’t a good idea to leave the club I was at mid-season’: Premier League boss admits to turning down opportunity to replace Jesse Marsch in 2023
