MacArthur played in the National Hockey League (NHL) with the Ottawa Senators, Buffalo Sabres, Atlanta Thrashers and Toronto Maple Leafs.

Prior to turning professional, MacArthur spent three seasons playing for the Medicine Hat Tigers in the Western Hockey League (WHL).

[1] He went unselected in the Western Hockey League (WHL) Bantam Draft when he was eligible, due in part to his short stature.

[1] With the numbers MacArthur put up in bantam hockey, he was able to secure a tryout with the Medicine Hat Tigers, but was the club's final cut heading into the 2001–02 season.

After starting the 2006–07 season in Rochester for a second year,[7] MacArthur made his NHL debut for Buffalo on December 19, 2006, against the Montreal Canadiens.

After the season, the Sabres tendered MacArthur a qualifying offer to retain his rights; he subsequently signed a two-year deal with the club in July 2009.

"[17] Maple Leafs captain Dion Phaneuf, one of MacArthur's teammates at the 2005 World Junior Championships, was influential in the decision to sign with Toronto.

At the end of his first season with the Maple Leafs, he signed a two-year contract extension at $3.25 million per annum on July 5, 2011, thereby avoiding salary arbitration with the club.

[20] On July 5, 2013, after his contract had expired with the Maple Leafs, MacArthur signed a two-year, $6.5 million deal with Toronto's Ontario rivals, the Ottawa Senators.

[21] On August 19, 2014, the Senators announced they had signed MacArthur to a five-year contract extension worth a total of $23.25 million—carrying a $4.65 million annual average value—set to start in the 2015–16 season.

On April 23, 2017, MacArthur scored the series-winning goal (on the powerplay for a 3-2 win 6:30 into overtime of game six) against the Boston Bruins in their first round playoff matchup.

[31][32] On November 14, 2017, Senators general manager Pierre Dorion stated it was "highly doubtful" MacArthur would ever play another NHL game.

[citation needed] MacArthur made his international debut playing for Team West at the 2002 World Under-17 Hockey Challenge, which was held in Manitoba.

[1] Clarke also has an uncle Ken MacArthur[37] who was selected by the Minnesota North Stars the eighth round (148th overall) of the 1988 NHL Entry Draft.