In the subsequent 1952–53 season, Toppazzini made his National Hockey League (NHL) debut with the Bruins, scoring 23 points in 69 games.

The following season, splitting time between Hershey and the major league club, he was traded to the Chicago Black Hawks for centre Gus Bodnar, and was subsequently dealt to the Detroit Red Wings in an eight-man multi-player deal, which at the time was the largest transaction in league history.

[2] Toppazzini remained with Boston for the next nine seasons, blossoming into a skilled two-way player while playing on a line with smooth centre Don McKenney and hard charging left wing Fleming Mackell; the trio was Boston's best line as they surged to the 1957 Stanley Cup Finals, knocking off the heavily favoured former champion Detroit Red Wings en route.

[4] Always a fan favourite, he won the Elizabeth C. Dufresne Trophy twice in a row, in 1956–57 and 1957–58, as the best performing and most popular Boston Bruin at home games.

[6][7] He finished his playing career in 1967–68 as the player-coach of the Port Huron Flags of the International Hockey League (IHL).

During the 1960–61 season, on October 16, 1960, Toppazzini substituted for Boston goaltender Don Simmons, who was injured with 30 seconds left in a match against the Chicago Black Hawks, in which the Bruins were losing 5–2.