Culpepper was born to a single mother, Barbara Henderson, who is the sister of former NFL linebacker Thomas “Hollywood” Henderson. While his mother was pregnant with him, she was serving time for armed robbery. Culpepper was adopted when he was a day old and raised as one of more than 15 children of the late Emma Lewis Culpepper, who worked in the correctional facility where his mother was held. They lived in Ocala, Florida, where Culpepper attended Vanguard High School. He played football, coached by Alex Castaneda, one of five finalists for the 2000 NFL High School Football Coach of the Year Award, as well as basketball and baseball. After his senior season in 1994, he was named Mr. Football in the state of Florida. In 2007, Culpepper was named to the FHSAA’s All-Century Team that listed the top 33 football players in the state of Florida’s 100-year history of high school football.

Culpepper was drafted in the 26th round (730th overall) by the New York Yankees in the 1995 Major League Baseball Draft but did not sign and chose to attend college.

In 2000 he was named Minnesota’s starting quarterback. He led the Vikings to victory in the first seven games of the season, and helped them finish 11–5 and advance to the NFC Championship game, where they were blown out by the New York Giants 41–0. During the season, Culpepper passed for 3,937 yards, 33 touchdowns and 16 interceptions. He also rushed for 470 yards and seven touchdowns. One of Culpepper’s most notable moments was against the Buffalo Bills when he threw a pass across his body and the field to Randy Moss for a 39-yard touchdown pass, although the pass was at least 60 total yards. At the end of the year, he was selected to his first Pro Bowl. Randy Moss, wide receiver for the Vikings, said that Culpepper was one of the most talented quarterbacks he has ever seen following the 2000 season.

Culpepper struggled over the next two seasons beginning in 2001 throwing 14 touchdowns to 13 interceptions. The Vikings finished the season 5–11. Culpepper started all 11 games in which he appeared, missing the final five games of the season with a knee injury he suffered in a game against the Pittsburgh Steelers on December 2. He completed 60 percent of his passes or better in nine of his 11 outings, including twice when he surpassed the 70.0 mark and had a passer rating of 100.0 better in two contests where the Vikings were 1–1 in those games. Culpepper’s rushing total ranked third among NFL QBs, trailing only Pittsburgh’s Kordell Stewart (537) and Philadelphia’s Donovan McNabb (482). Perhaps his most notable performance during this campaign occurred during the 20–16 comeback win over the Tampa Bay Buccaneers. On the run, Culpepper barreled into Derrick Brooks and Shelton Quarles, but was the first player up after the 8-yard score.

Culpepper continued to struggle in 2002, throwing 18 touchdowns to 23 interceptions and leading the Vikings to a 6–10 record. Some attribute this to his appearance on the cover of the Madden NFL 2002 video game, where he subsequently proceeded to have the worst year of his career until 2005, keeping with the superstition of the “Madden Curse”. Culpepper went on to win the EA Sports Madden Bowl title among NFL players during the 2003 offseason.

His ten rushing scores led all NFL QBs in 2002, and also marked the sixth-highest total by a QB in NFL history trailing only Cam Newton (14 for Carolina in 2011), Steve Grogan (12 for New England in 1976), Johnny Lujack (11 for Chicago in 1950), Tobin Rote (11 for Green Bay in 1956), and Kordell Stewart (11 for Pittsburgh in 1997).

Culpepper made a comeback in 2003, leading the Vikings to a 9–7 record, although they missed the playoffs. He passed for 3,479 yards, 25 touchdowns, and only 11 interceptions, and earned his second trip to the Pro Bowl.

Culpepper enjoyed his best statistical season as a professional in 2004 and, though they were only 8–8, the Vikings reached the playoffs for the second time under Culpepper. Passing for a league-leading 4,717 yards, a Viking-record 39 touchdowns, and only 11 interceptions, Culpepper was named to his third career Pro Bowl. Culpepper also broke Dan Marino’s NFL record for combined passing and rushing yards, amassing 5,123 total yards. His 2,323 rushing yards from 2000–2004 also made him only the fourth quarterback in NFL history to run for more than 2,300 yards in a five-season period. (Michael Vick had 3,570 from 2002–2006; Randall Cunningham had 3,232 from 1986–1990; and Steve McNair had 2,387 from 1997–2001). Culpepper’s career rushing average of 26.1 yards per game is fourth-best among quarterbacks in NFL history. Only Vick (47.3 yds/g), Cunningham (30.6 yds/g), and Bobby Douglass (29.8 yds/g) have averaged more rushing yards per game during their QB careers. After the 2004 season, Culpepper said the game had “slowed down” for him, saying

His first two games of the 2005 season were disappointments, as the Vikings went 0–2 while Culpepper threw no touchdown passes, eight interceptions, and fumbled twice which many attribute to his relatively small hands. Culpepper rebounded in the third week, throwing for 300 yards and three touchdowns while beating the New Orleans Saints. In 2005, he had six touchdowns, twelve interceptions, and five fumbles before getting injured in the seventh game (only winning two games). On October 30, he suffered a knee injury during a 38–13 loss to the Carolina Panthers. Culpepper sustained damage to three of the four major ligaments in the knee: the ACL, PCL and MCL. He was placed on injured reserve and began rehabilitation treatment near his home in Florida. Backup Brad Johnson took over in the Carolina game and after losing that one, they won the next six straight games and the team ended up with a 9–7 record. Daunte’s final career won-loss record as a starter for the Vikings was 37–40 (48.1% winning percentage).

On December 14, 2005 Culpepper and three other players were charged with indecent conduct, disorderly conduct and lewd or lascivious conduct for their involvement in the 2005 Minnesota Vikings boat cruise scandal, according to court papers and news reports. The maximum penalty they could have faced was 90 days in jail. His defense contended there was racial discrimination among the prosecution. On April 4, 2006, however the charges against Culpepper were dropped owing to a lack of probable cause.

On November 30, 2006, Culpepper underwent arthroscopic surgery on his previously injured knee to remove a piece of loose cartilage that was causing Culpepper difficulty. On December 12, 2006 Culpepper was placed on Injured Reserve, officially ending his 2006 season. Head coach Nick Saban stated that although Culpepper was making progress in his rehabilitation, he and the medical staff felt it would be difficult for Culpepper to play in the next three weeks.

On December 25, 2006, Steve Young appeared as a guest announcer during the Dolphins’ second to last game and criticized Culpepper’s work ethic. Culpepper saw this on TV from his box suite at Dolphin Stadium and immediately walked down to the ESPN booth and waited for Steve Young to finish, then Daunte confronted Young about it and said he has not missed any meetings and that’s not who he is. Young apologized and said though he heard Culpepper had been missing meetings he should have checked with Daunte first before repeating it. After the season coach Saban left for a head coaching job at the University of Alabama. On January 21, 2007 the South Florida Sun-Sentinel reported that despite public assertions by Saban, privately his decision to bench Culpepper actually had little to do with his knee and more to do with his head.

On June 5, 2007 the Dolphins completed the long-awaited trade for Trent Green; a few hours before the Green trade became official, the Dolphins told Culpepper they “are going in a different direction at the QB position,” according to Culpepper, who resisted that plan.

Culpepper was first and most often linked to the Jacksonville Jaguars, but Jaguars head coach Jack Del Rio said he did not feel Culpepper would be a good fit. Culpepper worked out for the Tampa Bay Buccaneers soon after his release, but was not acquired by the team. On July 31, Culpepper signed a one-year contract with the Oakland Raiders, as an insurance policy by the Raiders as they struggled to sign number-one draft pick JaMarcus Russell, with whom they were engaging in contract negotiations. In 2007, Culpepper replaced the injured Josh McCown for the Raiders matchup against his former team, the Miami Dolphins. Culpepper finished the game with two passing and three rushing touchdowns. Culpepper started a total of six games for Oakland. Prior to the Week 13 game against the Denver Broncos, Culpepper was nursing a sore quadriceps. He said he suffered the injury during the Week 12 game against the Kansas City Chiefs but it did not begin to bother him until Wednesday. Some sources said he suffered the injury when he ran a race with Oakland cornerback Stanford Routt, a college sprinter, after practice but head coach Lane Kiffin said “I don‘t know anything about that.” Due to his injury, Culpepper did not play in another game that season and was placed on injured reserve on December 26.

Culpepper visited the Green Bay Packers on April 23 and 24, 2008. He would later turn down the offer from the Packers, $1 million for a one-year contract, claiming the deal was not good. He said he was in contact with a few other teams. In July 2008, it was reported that the Detroit Lions were interested in signing Culpepper, but they never made an offer to him. He worked out with the Pittsburgh Steelers in August 2008, but the Steelers elected to sign Byron Leftwich instead to replace the injured Charlie Batch. On August 29, 2008, Culpepper then changed his mind and stated that he would consider a backup role in Green Bay if they were still interested in him, but the team did not put forth an offer.

On September 4, 2008, Culpepper announced his retirement. He expressed his frustrations with the NFL in a brief retirement letter. The main reason of his retirement was because he felt he could still be a starting quarterback in the NFL.

On November 2, 2008, ESPN reported that he had agreed to terms on a two-year deal contract with the Detroit Lions and would join the team the following week. After passing a physical, Culpepper officially signed with the Lions on November 3. The Lions assigned Culpepper number 11, the number Roy Williams had worn before he was traded to Dallas on October 14. Culpepper played four games with the Lions before suffering a shoulder injury. On December 28, 2008, the Lions became the first team in NFL history to go 0–16. The only other teams since the AFL–NFL merger to have a winless season were the 1976 Tampa Bay Buccaneers, who went 0-14 (the NFL did not extend the schedule to 16 games until 1978), the 1982 Baltimore Colts, who went 0–8–1 during that strike-shortened season, and subsequently the 2017 Cleveland Browns, who went 1–31 over the 2016 and 2017 seasons.

On February 16, 2009, the Lions reached an agreement with Culpepper for a restructured deal that would keep him on the team in the second year of his two-year contract. He had been due a $2.5 million roster bonus later in February prior to the restructuring.

On September 7, 2009, it was reported first overall draft pick Matthew Stafford was named the starter for the Lions regular season opener against the Saints. During preseason, Culpepper had suffered another injury (foot). Culpepper said he will respect Matthew Stafford as starter. However, he said he’s not against a trade.

On December 14, 2009, Culpepper played in what the Detroit Free Press headlined as “Lions suffer one of their biggest defeats in history.” Played in Baltimore, the Ravens won the game 48–3. In week 14, versus the Arizona Cardinals, Culpepper was benched in favor of third string QB Drew Stanton after a poor performance.

Culpepper signed with the Sacramento Mountain Lions of the United Football League on June 7, 2010. The signing reunited Culpepper with Dennis Green, his former head coach in Minnesota, and Mike Kruczek, his former head coach at the University of Central Florida. Culpepper was named UFL Offensive Player of the Week, twice in the 2010 season. His best game came in week 2 beating the Florida Tuskers 24–20, throwing for 374 yards and 2 passing touchdowns and one rushing touchdown. In April 2011, Culpepper was placed on the protected players list, for the 2011 UFL season.

On August 14, 2011, San Francisco 49ers head coach Jim Harbaugh announced that Culpepper was working out for the team on the following Monday to possibly add him to the 49ers roster. However, the 49ers opted to sign Culpepper’s former Oakland Raider teammate Josh McCown instead.