The 31-year-old is chasing his first European Tour victory since 2012 and made a superb start in Turin, with Bernd Wiesberger also avoiding any dropped shots to join him atop the leaderboard.
Molinari - looking to enhance his claims as one of Paul McGinley's captain's picks for team Europe at next month's Ryder Cup - set his marker out early by registering birdies on the opening two holes.
The Italian was particularly impressive with his approach play and collected four birdies on his way to a 32 on the back nine, all four putts coming from within 10 yards as he signed for a six-under par.
Wiesberger, who teed off in the group straight after Molinari's, was able to match that effort.
The Austrian partnered Rory McIlroy in the final round of the US PGA Championship and once more showed his quality by storming out of the blocks to go three under through the first four holes.
Back-to-back birdies at 11 and 12 followed and he picked up another shot at 15.
American John Hahn was one of five players who were tied for third at the close of play.
The 25-year-old - who started on the 10th - fired home six birdies and one bogey and even held the clubhouse lead at one stage.
Stephen Gallacher endured a frustrating day as he bids to force his way into an automatic spot for the Ryder Cup.
The Scot is the only man who can usurp Graeme McDowell - absent from the tournament due to the birth of his child - on the world points list.
Birdies at the 11th and 12th - his second and third holes - saw him make a bright start, but by the end of the round his four birdies had been negated by as many bogies to leave him six shots off the pace.
"I'm a bit disappointed because I threw away a couple of shots midway through my round," Gallacher told the European Tour's official website.
"It's okay for the first day and I am only one good score away from the top of the leaderboard."
Defending champion Julien Quesne started with a two-over-par 74 and has work to do to make the weekend.