After playing one more season for Granby, he joined the Sherbrooke Canadiens of the American Hockey League (AHL) in time to make his professional debut in the spring of 1988, playing three regular season games and four playoff games.

He also played in 14 playoff games on Montreal's way to the 1989 Stanley Cup Finals, a loss against the Calgary Flames.

Perhaps his most famous performance happened in game two of the 1993 Stanley Cup Finals on June 3, 1993, when he scored all of Montreal's goals in a 3–2 overtime win over the Los Angeles Kings in a game also marked by Marty McSorley's illegal stick penalty.

On February 9, 1995, Desjardins was traded to the Philadelphia Flyers along with John LeClair and Gilbert Dionne in exchange for Mark Recchi and a third-round pick in the 1995 NHL entry draft (Martin Hohenberger).

His original team, Montreal, was interested in signing him for the 2006–07 season, but Desjardins opted to retire as a Flyer on August 10, 2006.