A 6-foot-5, 220-pound defenseman who moves well and loves to hit, Zadorov was selected by the Buffalo Sabres with the No. 16 pick in the 2013 NHL Draft.

On Oct. 23, 2013, an 18-year-old Zadorov scored his first NHL goal against the Boston Bruins in his second NHL game. He played five more NHL games that season before being returned to juniors in early November, but made an impression with a seven-hit game against the Florida Panthers and a five-hit outing against the Anaheim Ducks.

At 19, Zadorov played the entire 2014-15 with the Sabres, and his 134 hits led all rookie defensemen in the NHL and ranked fourth on the Sabres. His 15 points put him sixth among rookie NHL defensemen in scoring and second in scoring among Buffalo defensemen.

On Dec. 13, 2014, Zadorov became the youngest defenseman in Sabres history to score an overtime goal, at 19 years and 242 days. The goal 29 seconds into OT gave the Sabres a 4-3 win against the Florida Panthers, and Zadorov, who assisted on Buffalo's first goal of the game, his first multipoint game in the NHL.

The Colorado Avalanche acquired Zadorov from Buffalo in the June 26, 2015 trade that sent forwards Ryan O'Reilly and Jamie McGinn to the Sabres. With the Avalanche, he has continued to be a crease-clearing, big-hitting presence.

The Avalanche traded Zadorov to the Chicago Blackhawks on Oct. 10, 2020, and the Blackhawks traded him to the Calgary Flames on July 28, 2021. He was traded to the Vancouver Canucks by the Flames on Nov. 30, for a third-round pick in the 2026 NHL Draft and a fifth-round selection in the 2024 NHL Draft.

Zadorov signed a six-year contract with the Boston Bruins on July 1, 2024.

In 2013, Zadorov helped London win the Ontario Hockey League championship and scored two goals in five games in that year's Memorial Cup. The next year he won a bronze medal with Russia at the World Junior Championship while leading Russian defensemen with four goals and five points in seven games.