Sergei was drafted by the Detroit Red Wings in the 1989 NHL Entry Draft, fourth round, 74th overall. In his pre-NHL days, he played for CSKA Moscow on a line with future superstars Pavel Bure and Alexander Mogilny and was drafted in the same year as Bure and a year after Mogilny. In 1990, while CSKA Moscow was in Seattle for the Goodwill Games, Fedorov quietly slipped out of his hotel room and onto an airplane bound for Detroit. Thus, he became one of many NHL stars to have defected from the Soviet Union to play in the NHL.

Arguably, his greatest season was in the 1993-94 NHL season when he won that year's Hart Memorial Trophy (being the first European-trained player to do so), Frank J. Selke Trophy and Lester B. Pearson Award, and finished second in scoring behind Los Angeles' Wayne Gretzky with 56 goals and 120 points. He would also win another Frank J. Selke Trophy in 1996, after compiling another 100-point season with 39 goals and 107 points. One year later, he was a member of the Red Wings' first Stanley Cup championship team since 1955, contributing 20 points in 20 playoff games for Detroit. He would go on to win two more Stanley Cups in 1998 (with 30 points in 24 playoff games) and 2002, both with the Red Wings. He also won a bronze medal with Russia in the 2002 Winter Olympics in Salt Lake City, and a silver medal in the 1998 Winter Olympics in Nagano.

In 1997, Fedorov earned $20 million, the highest salary ever paid to an NHL athlete. His base salary was reportedly only $1 million but his contract contained large bonuses.

In recent years, Fedorov has been criticized for a lack of heart (especially in an injury-riddled 1999-2000 season, when he only appeared in sixty-eight games). Other detractors also suspect that Fedorov was dissapointed that his achievements were passed over. Wings Captain Steve Yzerman regularly recieved far more recognition from fans and media; an example was the 1998 postseason where Fedorov had 30 playoff points to Yzerman's 24, but Yzerman won the Conn Smythe Trophy.

Nonetheless, in the stifled offensive landscape of the inter-lockout NHL, Fedorov still managed to average close to a point a game, and, except for three seasons, had never scored less than thirty goals. In the 2003 offseason, he signed with the Anaheim Mighty Ducks, where he played from 2003-2005. He was traded to the Columbus Blue Jackets on November 15, 2005. It was with the Ducks that Fedorov picked up his 1,000th point, becoming the first Russian-born and fifth European-born player to do so. Fedorov, as a Blue Jacket, also played his 1,000th NHL game on November 30, 2005 becoming the 13th European-born player to reach 1,000 NHL games and the 205th player overall to do so.

He was also married, briefly, to Anna Kournikova before her relationship with Enrique Iglesias (see[[1]]).

His younger brother, Fedor Fedorov is an ice hockey player with the New York Rangers' AHL team, the Hartford Wolf Pack.

On 27 May 2006 he took part in Soccer Aid at Old Trafford, a charity football match held between England and the Rest of the World. He was a member of the Rest of the World team which comprised football legends and other celebrities.