Dutch rider De Kleijn held off Movistar's Fernando Gaviria, a stage winner at the Tour de France and Giro d'Italia, in a tight finish in Orbassano just outside Turin. Casper Van Uden (21) of Team DSM finished third.
The one-day race is considered the last warm-up before Milan-San Remo on Saturday, the first Monument of the season.
"I had a great lead out, I went through the corner at 900 metres, got in a good position and then I knew I had a big chance," said De Kleijn to broadcaster RAI.
"We did this with the whole team, they were working the whole day for me and kept me out of the wind. It's a big team effort."
There was some controversy as after being brilliantly position by his team Tudor, De Kleijn appeared to deliberately block Gaviria by swerving towards the roadside banners, making any overtaking attempt hazardous.
"I think I did nothing wrong, I think there was enough space," added De Kleijn.
De Kleijn's win was his sixth as a professional, and his first since the first stage of the Four Days of Dunkirk in May last year.
Elsewhere in the cycling world on Wednesday, Tim Merlier (30) won Nokere Koerse men's race with Lotte Kopecky (27) taking home the women's edition just days after the tragic death of her older brother Seppe.
