Zetterberg was selected by the Detroit Red Wings 210th overall in the seventh round of the 1999 NHL Entry Draft. Detroit was under criticism at the time for “mortgaging its future”, trading away many of its earlier picks in the 1999 Draft. After playing for Timrå IK of the Swedish Elitserien for the 2000–01 and 2001–02 seasons, Zetterberg signed his entry-level contract on 16 May 2002. Zetterberg came to Detroit to play his rookie season in the NHL in the 2002–03 season.

Zetterberg made his NHL debut against the San Jose Sharks on 10 October 2002, at the Joe Louis Arena. He played in 79 games his rookie season, scoring 22 goals and 22 assists for 44 points, leading all first-year players. Zetterberg finished the season as runner-up for the Calder Memorial Trophy as rookie of the year behind St. Louis Blues defenceman Barret Jackman. In his second season, Zetterberg nearly matched his rookie stats despite missing 21 games due to a broken leg suffered against the Vancouver Canucks early in the season on 5 November 2003. Due to the owners’ lockout the next season, Zetterberg returned to Sweden to play for Timrå IK in 2004–05, leading the Elitserien in scoring with 50 points in 50 games.

With the announced retirement of Steve Yzerman during the season, Swedish newspaper Aftonbladet speculated that Zetterberg might take over the captaincy for the Red Wings, but Lidström was instead named Yzerman’s successor while Zetterberg was named an alternate on the day of the Red Wings’ 2006–07 season opener. That season, Zetterberg was selected for the 2007 NHL All-Star Game, but withdrew to rest an injured wrist. Later in the year, Zetterberg scored his 100th career goal against the Phoenix Coyotes on 8 February 2007, prompting Coyotes head coach Wayne Gretzky to comment that Zetterberg is “probably the most underrated player in the league.” Nine days later, on 17 February, in another game against the Coyotes, Zetterberg picked up his first career hat-trick, all power play goals, and added an assist on an empty-net goal by Jason Williams for a four-point game. He finished the season with 68 points in his injury-shortened 63-game season.

Zetterberg started his youth league career playing games for the Njurunda Sports Club, as did Fredrik Modin. In 2008, the club renamed their arena—until then known as Njurunda Ishall—to Modin & Zetterberg Hall in their honor. When Zetterberg was 15 years old he left Njurunda for Timrå IK. Zetterberg caught the attention of the Red Wings’ Assistant General Manager Jim Nill and Director of European Scouting Håkan Andersson during a tournament in Finland. While Andersson was trying to point out Mattias Weinhandl, Nill could not help noticing “this little Zetterberg guy who always seemed to have the puck.”

With the 2008 Stanley Cup championship, Zetterberg became a member of the Triple Gold Club. The term is used for an exclusive group of ice hockey players who have won Olympic gold, World Championship gold, and the Stanley Cup. Zetterberg is one of 25 members of this exclusive club, a club that also includes several teammates and his current head coach. Zetterberg along with teammates and fellow Swedes Niklas Kronwall and Mikael Samuelsson are the fastest to accomplish this feat, requiring only two years, three months and ten days.

In the final year of his contract in 2008–09, Zetterberg agreed to a 12-year, $73 million contract extension with the Red Wings on 28 January 2009. The deal is the longest and most lucrative in franchise history. Zetterberg recorded 11 goals and 13 assists for the Red Wings during the 2009 Stanley Cup Playoffs that saw them reach Game 7 of the Stanley Cup Finals, only to lose to their 2008 opponent the Pittsburgh Penguins.

In 2009, film-makers Greg DeLiso and Jakob Hawkins released a video series called “Fun With Henrik Zetterberg.” The videos center around a bumbling Henrik Zetterberg look-alike (played by Hawkins) and were positioned as spec commercial spots for the NHL and their affiliates. Although the spots were never picked up, the videos themselves went viral, garnering over 50,000 views in two days. The success of the videos spawned “Fake Henrik Zettererg,” a twelve-episode web series authored by DeLiso and Hawkins. The series was launched on 26 October 2011 and has been featured on Yahoo Sports and The Huffington Post. The series featured Kevin Brown and Austin Pendleton.

In the summer of 2008 he became engaged to Emma Andersson, a Swedish model and TV host. On 23 July 2010, Zetterberg married his fiancée near the bride’s hometown in Mölle, Sweden.

On 15 January 2013, Zetterberg was named captain of the Red Wings, succeeding Lidström who had retired. Despite missing 13 games due to chronic back problems, he scored over 40 points through the first part of the 2013–14 NHL season. However, he sustained another back injury during the 2014 Winter Olympics and underwent surgery, causing him to miss an estimated two months of the season while the Red Wings pursued a berth in the NHL playoffs for the 23rd straight year. Zetterberg returned for the final two games of the 2014 Stanley Cup playoffs as the Red Wings were eliminated in the Eastern Conference Quarterfinals by the Boston Bruins. He elected not to play for Sweden in the 2014 IIHF World Championship to further recuperate from his back injury.

On 6 November 2015, Zetterberg recorded his 300th career goal against James Reimer of the Toronto Maple Leafs. He became the seventh Swedish player to reach the 300 goal plateau, and the fifth player in Red Wings franchise history to have 300 goals and 800 points, following Gordie Howe, Alex Delvecchio, Steve Yzerman, and Sergei Fedorov.

On 20 August 2015, Andersson gave birth to their first child, a son named Love (pronounced Loo-VEY).

Zetterberg was named to Team Sweden for the 2016 World Cup of Hockey. On 11 August 2016, Zetterberg was named captain of the team. However, on 1 September, Zetterberg withdrew from the tournament due to a knee injury. He was replaced by Calgary Flames forward Mikael Backlund and Henrik Sedin was named the captain in his place.

On 9 April 2017, he played his 1,000th game for the Red Wings organization, as well as became the seventh in franchise history in total points.

During the 2017–18 season, Zetterberg reached several milestones. On 24 February 2018, he recorded his 335th career goal, tying him with Ted Lindsay for fifth all time in goals scored in franchise history. On 29 March 2018, he recorded his 954th career point, tying him with Sergei Fedorov for fifth all time in total points in franchise history.

On September 14, 2018, Red Wings general manager Ken Holland announced that due to a degenerative back condition, Zetterberg would be unable to continue with his NHL career. However, due to Zetterberg having 3 years left on his contract at the time of the announcement, he is not fully retired.