After starring locally, Brendan was drafted by the London Knights of the Ontario Hockey League in 1985. He spent two outstanding seasons with the Knights.

Shanahan was drafted second overall by the New Jersey Devils in the 1987 NHL Entry Draft and joined the team that fall. As an 18-year-old rookie, Shanahan collected 26 points in 65 games. The following season (1988-89), he improved to 22 goals and 50 points, but it was in his third NHL season that Shanahan emerged as a point-per-game producer with 72 points (including 30 goals) in 73 games.

After four seasons with New Jersey, Brendan became a restricted free agent following the 1990-91 season, and subsequently signed with the St. Louis Blues, who surrendered Scott Stevens for the opportunity. In his second season with the Blues, Shanahan exploded in 1992-93 with 51 goals and 94 points. In 1993-94, he collected personal bests in goals (52), assists (50) and points (102). He finished eighth in scoring and earned selection to the NHL's First All-Star Team.

After three seasons in St. Louis, Brendan was traded to the Hartford Whalers for Chris Pronger in July 1995 and was introduced as the team captain. He scored 44 goals and 78 points in his only full season in Hartford. Two games into the following season, Brendan and Brian Glynn were traded to the Detroit Red Wings for Paul Coffey, Keith Primeau and a first-round draft pick. He finished the season with 47 goals and 88 points, tenth best in the league that season. Through the playoffs, Shanahan contributed 17 points as the Red Wings captured their first Stanley Cup championship since 1955. Shanahan and the Red Wings repeated as Stanley Cup champions in 1997-98.

Brendan scored 41 goals and 78 points in 1999-2000, and was awarded selection to the NHL's First All-Star Team for a second time. He made the Second All-Star Team in 2001-02, scoring 37 goals and 75 points. During that season, Brendan scored his 1,000th point and 500th goal. He then added 19 more points as the Red Wings went on to win the Stanley Cup.

In 2002-03, Shanahan scored 30 goals and 68 points. At the annual NHL Awards, he was named winner of the King Clancy Memorial Trophy as recognition of his humanitarian efforts.

Following the NHL lock-out in 2004-05, Shanahan scored 40 goals and 81 points, good for third in points among the Red Wings. After nine very successful seasons in Detroit, Brendan became a free agent following the 2005-06 season and signed a one-year deal with the New York Rangers. Early in the 2006-07 season, he scored his 600th career goal. Shortly afterwards, Shanahan was recipient of the inaugural Mark Messier Leadership Award, a monthly honour (at the time) presented to a player who best exemplifies leadership skills on and off the ice.

Brendan played two seasons with the Rangers. Without a contract, he sat out the first part of the 2008-09 season. Then, on January 10, 2009, he agreed to join the New Jersey Devils for a second stint that lasted one season.

On November 17, 2009, Shanahan officially announced his retirement after 21 years in the NHL. Shanahan said, "I would like to thank my family and all of the friends who have helped me achieve and maintain my childhood dream of playing in the National Hockey League. While I always dreamed of playing in the NHL, I can't honestly say that I would have ever imagined that I'd be this fortunate and blessed. I would like to sincerely thank everyone who has helped me fulfill this dream." Through 1,524 regular season games, Brendan Shanahan scored 656 goals and 698 assists for 1,354 points. He also earned 2,489 minutes in penalties. In playoff competition, he scored 60 goals and 74 assists for 134 points in 184 games, while also serving 280 penalty minutes. Also of note are that Brendan had nineteen consecutive seasons scoreing 20 or more goals. He is also the only NHL player to have scored 600+ goals and 2,000+ penalty minutes.

Shanahan's contributions extend beyond the National Hockey League. In international play, Brendan was a member of Team Canada at the World Junior Championships in 1987, helped his team win a gold medal at the Canada Cup in 1991, was a member of the gold medal championship won by Canada at the International Ice Hockey Federation World Championships in 1994, won a silver medal at the 1996 World Cup of Hockey, was a member of Team Canada at the 1998 Olympic Winter Games in 1998 and won a gold medal for his country in 2002 and played for Canada at the 2006 World Championships.

But Shanahan proved to be a leader off the ice, too. During the NHL lock-out in 2004-05, he engaged players, coaches and other influential voices in a two-day conference to discuss improvements to the flow and tempo of the game. These recommendations were presented to the league and to the NHL Players' Association.

In December 2009, Brendan was named the NHL's Vice President of Hockey and Business Development. In June 1, 2011, he was assigned the role of chief player disciplinarian for the National Hockey League.