[12][13] He was named in the start list for the 2016 Giro d'Italia, also finishing second in the Bretagne Classic that season.

Following a successful solo attack on the second to last climb of the race, Oude Kwaremont, he managed to keep the gap to the chasing group which included several of the pre-race favorites, including previous winners Alexander Kristoff and Peter Sagan, for the remaining 17 km.

[17] In 2021, Bettiol won his first Grand Tour stage on day 18 of the Giro d'Italia in a solo fashion seventeen seconds ahead of the chase group.

He also won the combativity award for stage ten of the Tour de France, after attacking from the breakaway before being caught with nine kilometers remaining.

In March 2024, he won Milano–Torino from a 30 kilometer solo ride, followed by taking fifth at Milan–San Remo three days later.