Bettiol (XDS Astana), who also soloed to win a stage in 2021, caught Andreas Leknessund as they reached the Ungiasca summit and left the Norwegian in his wake before powering away on the descent.
The Italian took a quick glance over his shoulder before raising his arms long before the line in celebration, and his girlfriend, a Verbania native, was there to hug him after the finish.
"Today, in theory I won already before the start because I had all my family here and my second family because, of course, my girlfriend and all her family are from Verbania," Bettiol said.
"Having all of them, my brother, my father, my mom, and all my really, really few people that have always been around me, it was already, for me, a victory but winning like this is something I will bring forever with me."
Leknessund (Uno-X Mobility) came in 26 seconds behind in second, with Belgian Jasper Stuyven (Soudal Quick-Step) winning a four-rider sprint to take third.
Eulalio (Bahrain Victorious) was at the head of the peloton which trailed in over 13 minutes behind the winner, to stay 33 seconds ahead of Jonas Vingegaard at the top of the General Classification.
A group of 15 riders built up a healthy lead over the peloton on the 189-km ride from Alessandria, and by the time the stage reached the first of two climbs with less than 25 km to ride, the gap was over 11 minutes.
The breakaway stayed together on the short ascent to Bieno before the longer, steeper Ungiasca climb brought the expected attack and four riders got away.
Leknessund made his solo bid, but Bettiol gave chase, and it was more frustration for the Norwegian who also came second best to Jhonatan Narvaez on stage eight.
"I knew every single corner in the last 50 km because sometimes I train here," Bettiol said.
"The fact that I knew the climb really helped me and that's how I won."
Saturday's stage 14 should bring more of a shake-up in the GC, with a 133-km mountain stage from Aosta to Pila.