Spezza played in the Ontario Hockey League for the Brampton Battalion in the team's opening season 1998-1999, despite being a year too young to enter the draft normally, as he was already living in the city. He was drafted 2nd overall in 2001 after Ilya Kovalchuk. This pick had originally belonged to the New York Islanders, but had been traded to Ottawa along with Zdeno Chara and Bill Muckalt for Alexei Yashin.

Spezza was a highly regarded prospect, but took some time to move to the NHL, playing with the Senators AHL affiliate, the Binghamton Senators, in Binghamton, New York. He was called up on a few occasions. During one stint with Ottawa he helped the team win critical games in the 2003 Playoffs. He played a full season with the Senators in 2003-2004, and had a solid year.

During the NHL lockout Spezza returned to the AHL and with 117 points was the highest scorer in the league by a considerable margin, and the first to record so many points in several years. He was awarded the Les Cunningham Award as the league's Most Valuable Player. With centres Radek Bonk and Todd White traded during the off season, Spezza began the 2005 season as Ottawa's first line centre, playing between superstar Dany Heatley and rookie Brandon Bochenski, Spezza's linemate in Binghamton. After Bochenski was sent down to the AHL, Senators captain Daniel Alfredsson took his place beside Spezza and Heatley. Other players who play on a line with Spezza and Heatley are Chris Kelly, and occasionally Antoine Vermette.

Spezza was a reserve for Team Canada at the 2006 Winter Olympics in Turin, Italy, but did not actually play.

During the playoffs Spezza played with an unbearable amount of pain but was still able to score 14 points in 10 games. He underwent successful back surgery after the playoffs and should be better then ever for the 2006-2007 season.