Fisher debuted with the Senators in 1999–2000 and recorded 9 points in an injury-shortened 32-game rookie season. He became known for his aggressive style of play and began to also show his penchant for offensive production as he improved to 18 goals and 38 points in his fourth season in 2002–03.

During the lock-out year of 2004–05, Fisher played overseas for EV Zug in the Swiss Nationalliga A. As NHL play resumed the next season, in 2005–06, Fisher emerged with 22 goals and 44 points, providing valuable secondary scoring for the Spezza-Heatley-Alfredsson line. He helped the Senators to a first seed in the Eastern Conference going into the playoffs, but they were defeated by the fourth-seeded division rivals Buffalo Sabres in five games in the second round. With a career-high plus-minus rating of +23 in the regular season, Fisher was nominated for the Frank J. Selke Trophy as the best defensive forward.

On February 10, 2011, Fisher was traded to the Nashville Predators in exchange for the Predators' 2011 first round draft pick (Stefan Noesen) and a conditional pick in 2012. The condition was that should the Predators were to win a playoff series, the Senators would receive a third-round pick, and a second round pick if the Predators won two or more playoff series. The Predators won their first round playoff but ultimately lost their second round series, meaning the Senators received a third-round pick. According to Fisher, although there were many trade deals for him, Ottawa GM Bryan Murray and Ottawa owner Eugene Melnyk had chosen to accept Nashville's offer so that Fisher could be closer to his wife, country singer Carrie Underwood

Fisher played his first game with the Predators on February 12, 2011, and scored an assist in a 5–3 win over the Colorado Avalanche. He scored his first goal as a Predator five days later, on February 17, against the Vancouver Canucks.

Fisher was the winner of the 2012 NHL Foundation Player Award, awarded to the NHL player who applies the core values of hockey — commitment, perseverance and teamwork — to enrich the lives of people in his community.