He was five behind going into the final round and nobody gave him a chance but he produced a grandstand finish, holing a 40-foot putt on the 72nd green for a 12-under-par winning total of 276 and a two-shot victory.
England's Matthew Fitzpatrick, who began the day five shots ahead of Molinari, managed to scratch out a 1-under par 71 to finish runner-up two shots back at 10-under par.
Sweeping left-to-right from just inside 44 feet away, Molinari, who went on to win the event, hit the putt with the flawless amount of pace to put him in position for his third PGA Tour title in the last eight months.
"And I can think of two things where I could have hit a couple of better shots maybe, but overall I just think it was just a little disappointing".
"To get it done here at Arnie's place knowing that my wife and the kids were watching back home in Italy, it was a special one, " he said.
In some sports (i.e. the volatile ones such as golf and baseball), entry percentage matters more than in other, more consistent ones (e.g. basketball). "I knew it was not going to be easy".
Harding was three shots off the lead at the start of the day and although he birdied three of the first four holes, bogeys at the sixth and seventh looked to have derailed his title challenge.
The world number six had a fruitless day on the greens, making just one putt outside 10 feet compared to five (and a chip in) from Molinari.
In a separate contest within the tournament, Sungjae Im, Sung Kang and Keith Mitchell gained the three positions on offer at this year's Open Championship to the leading three players in the event not otherwise exempt to the third major of the year. I've seen so many putts on TV like that and to do it yourself it's really incredible. Adam Hadwin fell off the leaderboard over the final two holes, going triple bogey, bogey to finish at two under.
The four-time PGA Tour victor came within a shot of the lead early in his round but a bogey at the par-4 9th started a poor run that included only one birdie, bogeys at the 12th and 17th, as well as a double-bogey six at the 15th. But no one got closer than two shots by day's end while Molinari waited patiently in the clubhouse for his cardigan fitting.
All that mattered was that it dropped, capping off a five-shot rally with a final round no one imagined on a fast Bay Hill course with putting surfaces that looked closer to white than green, making it hard for anyone to get it close to the hole.
Molinari has four victories worldwide in his last 17 starts over the last nine months. It turned out to be too much for anyone to catch him.
"Finding motivation was easy after a year ago", Molinari said. The Quicken Loans National on the PGA Tour. He played the final 28 holes on this fiery course without a bogey.
The popular Italian, who won the Open at Carnoustie last July and then became a folk hero by claiming five points out of five at the Ryder Cup, ended a quiet period in emphatic fashion with a stunning final-round 64 to win the Arnold Palmer Invitational.
"I kind of see the Claret Jug every day when I'm at home, so I'm used to seeing it", said Molinari, drawing a laugh in the media center.