As the weather got worse and rain started to fall, Vendrame took the brave decision to break away from the group on the descent and the Italian put some distance between himself and the chasing pack.
He had last won a Giro stage in 2021 and he crossed the line with one arm raised in the air, with Pelayo Sanchez finishing second nearly a minute behind while stage 17 winner Georg Steinhauser was third.
The peloton crossed the line nearly 16 minutes after Vendrame.
"I had been aiming for this stage since the start of the Giro. It was important to get into the day's breakaway and I tried to save energy the whole day," Vendrame said.
"I attacked on the descent, taking a risk, saw that I had a good lead and kept pushing. It's a special emotion because I won close to my home."
Tadej Pogacar of UAE Team Emirates continues to hold on to the maglia rosa jersey with a lead of seven minutes and 42 seconds over Daniel Felipe Martinez despite suffering a puncture.
Geraint Thomas is third and although he overtook the maglia rosa group, he crashed with about six kilometres to go and was forced to change his bike, with the group slowing down to allow the Welshman to rejoin.
Barring any calamities, Pogacar can virtually seal victory on Saturday - a 184 km mountain stage from Alpago to Bassano del Grappa - before Sunday's final stage in Rome, which has traditionally been a procession.
