His first professional team was Partizan Belgrade where he spent four seasons, making his debut in 2000–01. In the 2003–04 season, his last with Partizan, he averaged 13.4 points per game in the Euroleague. With Partizan, he also won three YUBA League championships in a row, and one Serbian Cup championship in the 2001–02 season.
On June 26, 2002, he was drafted with the 24th overall pick in the 2002 NBA draft by the New Jersey Nets. However, he didn't join the Nets for two seasons, continuing to play with Partizan Belgrade.
During the 2004–05 NBA season, Krstić logged an impressive rookie campaign for the New Jersey Nets, averaging 10.0 points, 5.3 rebounds and 0.84 blocked shots per game. He was honored as part of the All-Rookie NBA second team.
In his debut in the playoffs against the Miami Heat, Krstić averaged 18.3 points, 7.5 rebounds, and 1.0 assists per game; an exceptional performance for a rookie in the playoffs. This followed a greater trend where Krstić had consistently improved at a great pace as his rookie season progressed. He has a wide skill set for a big man, including refined post moves and a fantastic shooting touch from eighteen feet.
Throughout the 2005–06 season, Krstić's play had continued to rapidly improve. Three quarters of the way through the season, he averaged 13.4 points and 6.1 rebounds, and had become an integral part of the Nets offense. In the first round of the 2006 NBA playoffs against Indiana he averaged 18 points per game along with 7.1 rebounds.
In 2006–07 despite the rough Nets start, Nenad Krstić was averaging career highs in points (16.6), rebounds (6.8), and assists (1.8) before falling to the ground after tearing his anterior cruciate ligament in his left knee versus the L.A. Lakers at Continental Airlines Arena on December 22, 2006. His surgery was successful. Krstić was out for the rest of the 2006–07 NBA season, but returned ahead of schedule to start the 2007–08 NBA season.
His 2007–08 season was a disappointment, as his injury disrupted his play and confidence on the court and he was largely a liability. Krstić later stated in his blog that he felt he let the team down, and vowed to return to his old form at the start of the 08–09 season.
During the 2008 summer off-season, Krstić entered negotiations with the Russian Super League team Triumph Lyubertsy and eventually signed a 2-year contract (with the NBA an opt-out option) worth €6 million euros net income with them on July 29, 2008. He averaged 10.4 points and 5.1 rebounds per game in seven games in the Russian Super League and 13.3 points and 7.3 rebounds per game in 6 games in the EuroChallenge.
On December 19, 2008, two NBA league sources told ESPN.com that the Oklahoma City Thunder had agreed in principle to sign Krstić to a three-year offer sheet. On December 22, Krstić officially signed the offer sheet. The New Jersey Nets had seven days to match the offer, or Krstić would be free to join the Thunder. The Nets declined to match, and the Thunder waived Steven Hill to make room for Krstić.
He played for the first time in a Thunder uniform on January 7, 2009, versus the Minnesota Timberwolves, scoring six points and blocking 2 shots in 16 minutes.
On February 24, 2011, Krstić was traded along with Jeff Green and a 2012 first round pick to the Boston Celtics for Kendrick Perkins and Nate Robinson. In his first game as a Celtic, he recorded 9 points and 6 rebounds in a win against the Los Angeles Clippers on February 26.
On June 22, 2011, Krstić signed a two-year contract with the Russian powerhouse CSKA Moscow. Over the season, he averaged 14.2 points and 5.4 rebounds in 24.5 minutes per game in the Euroleague. That earned him his first selection for the All-Euroleague First Team. In the Euroleague Final against Olympiacos, CSKA Moscow lost by 61-62 after Georgios Printezis's buzzer beater in the last seconds of the game, securing his team second Euroleague championship in history.
After a good season with CSKA Moscow, there were rumors that he was considering a return to the Boston Celtics. However, on July 10, 2012, Krstić signed a new two-year contract with CSKA Moscow, including a team's option to extend him for one more season. At the end of the 2012–13 Euroleague season, Krstić was included for the second-straight time in the All-Euroleague First Team.2013–14 season
After slow start at the beginning of the 2013–14 season, caused by some private problems he was having outside basketball, by the time he was improving his performances. In December 2013 it was revealed that he is a candidate for FIBA Europe Player of the Year. Eventually, Tony Parker would go for the second straight award. In loss to his former club Partizan Belgrade, he played his best game of the season by scoring 27 points and grabbing 7 rebounds. He was named Euroleague MVP for month January, averaging fifth-highest 16.4 points, 6 rebounds and 21.6 in PIR. After beating Panathinaikos in the playoff series, CSKA Moscow lost in the semifinal of the Euroleague Final Four to Maccabi Tel Aviv. Shortly after failing to win the Euroleague for third straight year, the president of CSKA blamed Krstić and his Serbian teammate Miloš Teodosić for not putting enough effort over the season. Krstić finished his third Euroleague season with CSKA Moscow with the lowest averages of 9.6 points and 3.2 rebounds over 29 games. Shortly after the Final 4, CSKA was facing elimination in the VTB United League from Lokomotiv Kuban, travelling by 2-0 without home advantage. Krstić helped CSKA eventually win the series after big comeback and advance to semifinals, answering to previous critics of the club's president. Eventually, CSKA won the VTB United League by sweeping Nizhny Novgorod 3-0 in the final series.
In the late June, CSKA Moscow used option in his contract to part ways and allow him to sign with another team. In July 2014, weeks after signing with Anadolu Efes, he had an interview for Večernje novosti. He stated that Ettore Messina, former coach of CSKA Moscow, was "killing him as a player", putting him to play at unnatural to him power forward position, which affected on his performances over the last two seasons with the club.
On June 26, 2014, Krstić signed a two-year contract with the Turkish team Anadolu Efes. He came in the club just after Dušan Ivković was appointed as new head coach, with whom he worked in the national team for many years.2014–15 season
On November 2, 2014, he fractured his left forearm, after flagrant foul by Mutlu Demir, in a game against Pınar Karşıyaka and was estimated to return in 6 to 8 weeks. He returned on the court on December 24, in a game against Darüşşafaka Doğuş and scored 2 points.
As the season was reaching to an end, Anadolu Efes cemented 2nd position of the regular season in the Turkish League. However, they were stopped in the Euroleague after the quarter-final series 1–3 loss to the eventual champion Real Madrid.
On June 14, 2015, in a Game 3 of the Turkish League final series against Pınar Karşıyaka, he tore ACL on his right knee. The injury will keep him off-the-court for estimated 6 months.
Over the season, he averaged 12.4 points and 5.2 rebounds in 27 games played of the Turkish League. He also played in 19 Euroleague games, where he averaged 12.8 points, 5.1 rebounds and a career-high 1.4 assists per game.
On June 30, 2016, Krstić signed with Turkish club Galatasaray Odeabank for the 2016–17 season. On September 9, 2016, it was announced, that Krstić was forced to retire due to serious knee injuries.
Krstić played with the Serbia and Montenegro national team at the 2004 Summer Olympics and EuroBasket 2005.
As captain of Serbian national team he played at the EuroBasket 2009, where he won the silver medal and 2010 FIBA World Championship, where he won the fourth place. In the following year, he played at the 2010 FIBA World Championship where Serbia was defeated 99–88 by Lithuania in the game for the bronze medal. He represented national team at the EuroBasket 2011 in Lithuania where Serbia finished eighth and at the EuroBasket 2013 in Slovenia where Serbia finished seventh and qualified for 2014 FIBA Basketball World Cup. At the World Cup in Spain, Serbian national team took silver medal. Shortly after the final game of the tournament, he retired from the national team, after ten years of playing and six years of captaining.
He is married to his wife Tanja and has one daughter. Krstić, whose nickname is "Curly", was voted the 3rd most eligible bachelor by Serbia's version of People magazine. On August 19, 2010, in a game against Greece for the Acropolis International Tournament 2010, he participated in a fight between players and threw a chair at Greek Ioannis Bourousis. That resulted in his spending the night at the police station, from where he was released the day after. He stated in his defence that he thought Bourousis was a fan when he threw the chair at him. In the same fight Krstić attacked Greek player Sofoklis Schortsanitis a number of times from behind.
After the 2010 Serbia earthquake, Krstić and his Oklahoma City Thunder teammates donated $10,000 to help his hometown of Kraljevo, which was directly affected by the nearby calamity.
Note: The EuroLeague is not the only competition in which the player participated for the team during the season. He also played in domestic competition, and regional competition if applicable.