Nabokov, an only child, was born in Ust-Kamenogorsk (now called Oskemen), in the Kazakh SSR (now Kazakhstan). His father, Viktor, was a former professional hockey goaltender who played 18 years in both Russia and Kazakhstan before he retired in 1987. After his playing career ended, Viktor established a goaltending school in the city, which Nabokov later attended. His mother, Tatyana, worked as an engineer in a local factory. Nabokov first played hockey when he was six years old, taking up the same position his father had played.

Nabokov first played for his hometown team, Torpedo Ust-Kamenogorsk, spending three years with the club from 1991 until 1994. After his last season with the club he was selected in the 1994 NHL Entry Draft by the San Jose Sharks in the ninth round, 219th overall. Tim Burke, the Sharks’ scout, was originally scouting for a different goalie when he heard of Nabokov. The Sharks never saw Nabokov play before selecting him in the draft, and did not contact him until 1997. The following season Nabokov moved to join HC Dynamo Moscow, where he would spend the next three seasons. His first year with Dynamo they won the league championship It was after the 1996–97 season, which saw Nabokov help Dynamo reach the final of the European Hockey League, that he was contacted by the Sharks and offered a contract and come to North America.

When he moved to North America in 1997, Nabokov initially went by the name “John”, fearing that English speakers might have difficulty pronouncing his name.

Nabokov started the 1999–00 season with the Sharks affiliate, the Cleveland Lumberjacks of the International Hockey League (IHL). After 20 games with Cleveland, where he had a record of twelve wins, four losses, and three ties, Nabokov was recalled to the Sharks to serve as the back-up to Steve Shields, after Mike Vernon was traded. Nabokov made his NHL debut on January 1, 2000, in relief of Shields, against the Nashville Predators. His first start came January 19 against the Colorado Avalanche; Nabokov made 39 saves for his first shutout in a 0–0 tie. He finished with 11 games played for the Sharks during the 1999–00 NHL season, winning two and losing two.

Nabokov met his wife, Tabitha Eckler, shortly after he began playing in Kentucky. She was a college student and waitress at the time. They were married in 2001. They have two children together, daughter Emily (born in January 2004), and son Andrei (born on February 12, 2007).

In the second game of the 2000–01 season, Shields hurt his ankle, leaving Nabokov to become the starting goalie. He appeared in 66 games and had a record of 32 wins and 21 losses, and was named to the mid-season All-Star Game. In recognition of his play, Nabokov was named the winner of the Calder Memorial Trophy as the rookie of the year, and was named to the year-end All-Rookie Team; he also finished fourth in voting for the Vezina Trophy for best goalie in the league. He had similar success the following season, with 37 wins and 7 shutouts in 67 games, and on March 10, 2002 he scored a goal against the Vancouver Canucks, both the first European goalie to do so, and the first goalie to score a powerplay goal.

At the start of the 2002–03 season, Nabokov held out in a contract dispute. After making less than $1 million the previous two seasons, he felt he deserved an increase in salary, speculated to be around $4 million per season. He missed five games before the team signed him to a two-year contract worth slightly more than $3.5 million per season. Both Nabokov and the Sharks had a poor season, with the team missing the playoffs for the first time in six years, and Nabokov only winning 19 games, and finishing with a losing record. This was improved upon in 2003–04 though, as Nabokov’s 31 wins helped the team reach the playoffs again, where they reached the third round for the first time in team history. A further two-year extension signed in 2004 saw him earn almost $4.5 million per year.

Nabokov was considered one of the elite goaltenders in the NHL, and was often ranked as one of the top ten, if not top five goaltenders in the NHL by ESPN The Magazine and The Hockey News. However, the 2005–06 season was an off year for Nabokov, and his save percentage of under .900 was a big concern to the team. He was relegated to the role of backup goaltender behind Vesa Toskala. Despite his less-than-stellar play, Nabokov was signed to a four-year contract extension worth roughly $21.5 million in February 2006. The contract had a no-trade clause that was activated on the condition that San Jose made the playoffs.

During the first half of the 2007–08 NHL season, Nabokov started the first 43 games for the Sharks, however on January 13, 2008, in Anaheim he received his first day off when Thomas Greiss started his first NHL game. Nabokov was recognized as one of the “Three Stars” for the NHL in the last week of December 2007, along with Alexander Ovechkin of the Washington Capitals and Jaromír Jágr of the New York Rangers. In addition to that honor, Nabokov was named the “Sharks Player of the Month” by Seagate Technology in December. Since the 1996–97 season, Seagate Technology has recognized Sharks players who made contributions to further the team’s accomplishments and makes a donation of $2,500 to The Sharks Foundation on the players’ behalf. Nabokov holds the franchise-record for having won this award nine times.

Nabokov played in his second NHL All-Star Game on January 27, 2008. He stopped all eight shots that came at him, marking the first time since Nikolai Khabibulin’s period in the 2002 game that a goalie played an All-Star period where no goals were scored. He secured the scoreless period when he blocked both of Ilya Kovalchuk’s shots in the last minute of the second period. On May 4, during game six of the 2008 NHL Playoffs Western Conference Semi-Finals, Nabokov made what has been called one of the best glove saves in decades, when he saved a shot from Brad Richards of the Dallas Stars by sliding over from the other side of the post and gloving the puck. The save was reviewed for several minutes before making it clear Nabokov saved it before it went over the goal line. The game, which ended in a Dallas victory, lasted for four overtime periods and is the eighth longest game in the league’s history.

Nabokov recorded 41 wins for San Jose during the following season as the team clinched first overall in the Western Conference and the league. Despite this, San Jose was eliminated in the first round of the playoffs by eighth seed Anaheim Ducks, marking just the fourth time that an eighth seed team defeated a first seed team in the first round of the playoffs. On October 17, 2009, he played in his 500th career game, all played with the Sharks, and stopped 31 shots in a 4–1 win over the New York Islanders. On February 11, 2010, Nabokov stopped a career-high 50 shots en route to a 3–2 shootout victory against the Detroit Red Wings, which was also his 11th consecutive road victory, a new NHL record.

Once again a free agent, Nabokov signed a contract with the Detroit Red Wings on January 20, 2011; the Red Wings were one of the top teams in the NHL at the time, and Nabokov signed a contract for just $570,000 as a result. However as he had started the season in the KHL, NHL rules required him to be placed on waivers prior to joining the Red Wings, and thus be available at that salary to any team lower than them in the standings. He was subsequently claimed by the New York Islanders, who were one of the worst teams in the NHL at the time. As he had only signed with Detroit in hopes of playing in the playoffs that year, Nabokov refused to join the Islanders, stating that he didn’t make a lot of sense to him why they claimed him. The Islanders suspended Nabokov for failing to join the team, and he sat out the rest of the season.

In August 2011, Nabokov stated that he would be reporting to New York’s training camp. He played for the team the entirety of the 2011–12 season, wearing the number 20, and eventually took over the starting goaltender position. He got his first win with the team on October 15, 2011, against the New York Rangers. On January 14, 2012, Nabokov recorded his 300th career win against the Buffalo Sabres, becoming the 26th goaltender to reach the milestone. On March 21, 2012 he signed a one-year, $2.75 million contract extension to remain with New York for another season, followed by another one-year $3.25 million contract for the 2013–14 season.

After New York signed goaltenders Jaroslav Halak and Chad Johnson in the 2014 off-season, it became clear they didn’t have plans to re-sign Nabokov. On July 1, 2014, he signed a one-year contract with the Tampa Bay Lightning worth $1.55 million. After posting a 3–6–2 record as the team’s backup goaltender to Ben Bishop, he was placed on waivers around the midpoint of the season, February 1, 2015. Following his waivers clear, it was questioned as to whether he would report to Tampa Bay’s AHL affiliate or consider retirement. On February 9, 2015, Nabokov was traded back to the Sharks for “future considerations”. He announced his retirement on February 11, 2015.

In September 2015, Nabokov became a goaltending development coach and scout in the Sharks organization; in addition to the Sharks, he worked with the goaltenders on the team’s AHL affiliate San Jose Barracuda. On December 11, 2019, after head coach Peter DeBoer and his assistants were fired, Nabokov was named the Sharks’ goaltending coach under interim coach Bob Boughner.