During his 16 NHL seasons, he played for the Detroit Red Wings, New York Rangers, Boston Bruins, Philadelphia Flyers and Washington Capitals.

Following his collegiate career, he made his professional debut in the 1995 Calder Cup playoffs with the Adirondack Red Wings of the American Hockey League (AHL).

During which, he set the NHL record for the fastest two goals to start a game by one player on February 14 against the Florida Panthers.

[5] He then played for Linköpings HC of the Swedish Elitserien during the 2004–05 NHL lockout, scoring 26 goals and assisting on 13 others in 49 games.

Knuble recorded his first career hat trick on February 2, 2008, scoring all the goals in a 3–0 Flyers win over the Anaheim Ducks.

He has traveled to schools in New Jersey and Philadelphia teaching kids about hockey in his free time.

On July 1, 2009, Knuble signed a two-year deal worth $2.8 million a season with the Washington Capitals.

Knuble scored Washington's first goal in the second period of the 2011 NHL Winter Classic against Pittsburgh Penguins' goaltender Marc-André Fleury.

[10] Knuble is currently an assistant coach with the Grand Rapids Griffins, Detroit's minor league affiliate.