The teenager, who admitted to drawing inspiration from Edoardo Molinari's Gleneagles victory and Ryder Cup call-up, matched the lowest round of his short professional career by grabbing seven birdies for a seven under par 64.
After finishing 13th in The 2009 Open Championship and 36th at The Masters Tournament in April - leads England's Graeme Storm and Finn Mikko Ilonen by one.
Manassero is trying to become the youngest winner in European Tour history, but would happily settle for earning enough to avoid Qualifying School in November.
A top five finish could do that after receiving the sixth of the seven invitations he is allowed this season.
"It was a perfect round of golf and a great start to a tournament that is very important to me," said the Verona player, whose other start will be the Dunhill Links Championship in Scotland next month.
Asked about Molinari and his brother Francesco both making Europe's side for the coming match at The Celtic Manor Resort Manassero added: "It's a big inspiration for me and all the guys growing up in Italy.
"It's unbelievable what they are doing. I watched Edoardo's win on Sunday - it was beautiful."
Storm and Ilonen are also former British Amateur Champions and they have already gone on to European Tour success.
Winner of the Alstom Open de France three years ago, Storm came back from an opening bogey with seven birdies, while Ilonen, with victories in Indonesia and Sweden to his name, sank a bunker shot on his final hole to join him in second place.
"It was an entertaining round," said the Finn. "I didn't strike the ball the best but I managed to put a good score on the card.
"I had a couple of chip-ins coming in. On the last I holed out from the bunker for a four and it was a great way to finish with a 65.
"I had a chip-in on the fifth as well. It was a tricky pin there and I went over the green with the second shot and chipped in. I didn't have too many putts today."
Storm added: "I've been playing really nice for a while and it's been frustrating so it was nice to get a good round under my belt. The game is consistent but to be perfectly honest I haven't holed many putts for a while. That is my best putting round all year.
"I love the venue and the course is growing on me. If the ball trickles off the green and you make a bogey you have to smile and get on with it. There is no better place than Crans when the weather is like this."
Molinari, who is taking three weeks off after this event to rest and then prepare for his Ryder Cup debut, did not drop a stroke, but was lucky at the long 15th when his pulled third shot was pulled into the trees, but came out just short of the green.
He was playing with twice Open Champion Greg Norman, the 55 year old Australian managing a four over 75 on his long-awaited return 12 months after shoulder surgery.
Miguel Angel Jiménez, the other member of Europe's side in the field, had a 67, the same as Ryder Cup vice-captain Darren Clarke.
When Norman – golf’s legendary Great White Shark – stepped up to the first tee, he did so as the newest member of Omega’s family of brand ambassadors.
Omega and Norman made the announcement as the event got underway at the scenic Crans-sur-Sierre Golf Club.
Norman joins a roster of Omega ambassadors which includes fellow golfers Sergio Garcia and Michelle Wie, Olympic swimming legend Michael Phelps, actors George Clooney and Nicole Kidman, supermodel Cindy Crawford and astronaut Buzz Aldrin among others.