Blake began his professional hockey career by playing for the Waterloo Black Hawks of the United States Hockey League. He was then signed as a free agent by the Los Angeles Kings in 1999. He was later acquired by the New York Islanders in a trade with the Kings in January 2001. The Islanders sent a conditional pick in 2002 to the Kings for Blake.
Jason set career highs in goals and points during the 2005–06 season with 28 and 57 respectively. He recorded his 40th goal of the season against the Maple Leafs on April 5, 2007. Blake's strong play was recognized on an international level as he, along with Islander teammates Rick DiPietro and Mark Parrish, were part of Team United States at the Winter Olympics held in Turin, Italy in February 2006. Team USA was led by Peter Laviolette, Blake's former coach with the Islanders. Blake scored his 99th and 100th career NHL goals against the Chicago Blackhawks at the Nassau Veterans Memorial Coliseum on October 31, 2006. The milestone 100th goal came on the power play late in the 3rd period. Blake was also named an all-star for the first time in his career during the 2006-07 season, and went on to record 2 assists in the game itself.
At the end of the 2006–07 season, Blake became an unrestricted free agent. He eventually signed with the Toronto Maple Leafs to a 5-year contract worth $20 million. In Jason Blake's first season as a Toronto Maple Leaf, he played in all 82 regular season games. He scored 15 goals and added 37 assists for a total of 52 points. While he managed a considerable number of points, he struggled to score goals all season, despite having over 300 shots on goal, which was easily a career high. Blake did however win the Bill Masterton Trophy for preservation in the game of hockey at the end of the season.
In the 2008-09 season, Blake continued to consistently put numerous shots on opponents' nets, but was rewarded with few goals. His lack of scoring production was derided by new Maple Leafs coach Ron Wilson, who set Blake as a healthy scratch for a game in November, 2008. Blake did not respond well to the benching, but did not complain nor let his dissent affect his on-ice game.
On October 8, 2007, Jason Blake announced that he had been diagnosed with chronic myelogenous leukemia, a rare, but highly treatable form of cancer. The doctors said he should plan to live a long, healthy life. Jason continued to play for the Toronto Maple Leafs for the rest of the season. He was awarded, in part, the Masterton Trophy for his absolute dedication to his team and the sport in the face of this illness.