Kassian was selected by the Buffalo Sabres with the No. 13 pick in the 2009 NHL Draft, and the next year showed why he held such promise when he helped Windsor of the Ontario Hockey League win the Memorial Cup.

He would play 27 NHL games with the Sabres, who traded him to the Vancouver Canucks on Feb. 27, 2012.

In Vancouver, Kassian had productive spurts, scoring 14 goals and 29 points in 73 games in 2013-14. On July 1, 2015, Kassian was traded to the Montreal Canadiens in a deal that sent forward Brandon Prust to Vancouver. But Kassian never played a regular-season game for the Canadiens.

On Oct. 4, 2015, with the NHL regular season days from starting, Kassian broke his nose and a bone in his left foot when the vehicle he was a passenger in crashed into a tree in a residential Montreal neighborhood. The Canadiens traded him to the Edmonton Oilers for goalie Ben Scrivens on Dec. 28, 2015.

In 36 games with Edmonton the rest of the season, Kassian had three goals, eight points and 95 hits. He impressed the Oilers enough that they signed him to a one-year contract on May 19, 2016.

After playing at least 74 games during his next three seasons, Kassian signed a four-year contract with the Oilers on Jan. 29, 2020. He was then traded to the Arizona Coyotes on July 7, 2022, and played 51 games that season.

Kassian retired from the NHL on Oct. 26, 2023 after playing 661 regular-season games and 45 Stanley Cup Playoff games through 12 seasons. His 913 penalty minutes at the time ranked ninth among all skaters since he joined the League in 2011.