He attended Victor Valley High School in Victorville, California, and earned medals at the California State Wrestling Championships in 1987 and 1988. He placed second in 1987 and fifth in 1988. He was a member of the 1987 Victor Valley High School wrestling team state champions. In 1988 Henderson became a national junior champion in both Greco-Roman and freestyle wrestling.

Henderson was coached by Bob Anderson, of the defunct California Jets. He placed second at the California State Wrestling Championship in 1987 and Victor Valley won the team title. In 1988, he placed fifth in the state finals and several months later won national crowns in both freestyle and Greco Roman at the Junior Nationals in Cedar Falls, Iowa.

In Greco-Roman wrestling Henderson became the university national champion in 1991, 1993, and 1994. He was the national champion at the senior level in 1993, 1994, and 1997. He represented the United States in the 1992 and 1996 Summer Olympics and placed 10th and 12th, respectively.

Henderson competed at the World Wrestling Championships in 1994 and 1997, placing 12th and 7th respectively. Other notable accomplishments include a bronze medal at the 1995 Pan American Games and a gold medal in the 2000 Pan American Championships. At this competition Henderson upset Luis Enrique Méndez in the final.

Henderson began training in mixed martial arts in 1997, when he joined the Real American Wrestling team (RAW).

1997 saw Henderson make his debut in MMA, following in the footsteps of other wrestlers who were finding success in the sport. Henderson entered the Brazil Open Lightweight Tournament, which had a weight limit of 176 pounds, the lightest Henderson would ever compete at. It was a one-night tournament, featuring four competitors. After two relatively quick finishes, Henderson won the championship.

About eighteen months later, Henderson entered his third MMA tournament. This time the number of competitors was 32, and there was no weight limit for any of the fighters. The tournament would be held over the course of two nights. The first two rounds were held in late 1999, while the final three were in early 2000. The tournament was full of many notable competitors, and Henderson faced Gilbert Yvel, Antônio Rodrigo Nogueira, and Renato Sobral. Despite weighing in at 199 pounds, and routinely being outweighed by more than 30 pounds, Henderson won all five of his fights, and became the Rings: King of Kings Tournament 1999 champion.

Henderson began competing in Pride Fighting Championships in late 2000. He entered in three tournaments for the organization, winning the Welterweight (183 pounds) tournament at Pride Shockwave 2005 by defeating Murilo Bustamante by split decision. The opening two rounds of the eight-man tournament were fought at Pride Bushido 9, at which Henderson knocked out both Ryo Chonan and Akihiro Gono. Along with this tournament victory, he was awarded the Pride Welterweight Championship.

In 2006, Henderson lost a decision in a rematch against Kazuo Misaki. It was the first time in that he had lost a fight to an opponent who was under 205 pounds. Henderson’s final Pride bout was a rematch with Wanderlei Silva at Pride 33 in Las Vegas, Nevada on February 24, 2007, at which he scored a knockout victory to become Middleweight Champion (205 pounds), while still holding his Welterweight title. Henderson became the first fighter to hold titles in two different weight classes simultaneously in a major MMA organization. Overall, Henderson went 13–5 with Pride, with eight victories coming by stoppage.

On September 8, 2007, Henderson returned to the UFC to face light heavyweight champion Quinton “Rampage” Jackson at UFC 75 in London, England. In a closely contested fight that saw Henderson impose his will early, Jackson controlled the later rounds and won a five-round unanimous decision to retain his title and gain the Pride middleweight title.

On November 17, 2007, it was announced during the post fight at UFC 78 that Henderson would fight UFC middleweight champion Anderson Silva to unify the Pride welterweight (183 lb) and UFC middleweight (185 lb) championships. UFC 82 took place on March 1, 2008 and was held at the Nationwide Arena in Columbus, Ohio. Despite winning the first round, Henderson lost via submission at 4:52 of the second round by rear naked choke.

Henderson grew up on a ranch in Apple Valley, California. He started wrestling at a young age and started being noticed as a relentless competitor. When he entered high school he placed on the wrestling team with his brother Tom at Victor Valley High, which was coached by Sam Gollmyer and assisted by their father Bill Henderson and Joe Barrios. He is of Native American, English, Scottish and French descent. Henderson had previously been prescribed testosterone replacement therapy (TRT) after being diagnosed with low testosterone levels in 2007. However, TRT has no longer been allowed in UFC competition since 2014. After TRT was banned, Henderson said that he quit using TRT “cold turkey”.

Henderson returned to the light heavyweight division to face former UFC Middleweight champion Rich Franklin on January 17, 2009, at UFC 93 in Dublin, Ireland. Henderson won the fight via a split decision following an eye-poke in the third round that many, including Franklin, thought was intentional. He was subsequently selected to lead Team U.S. on season 9 of The Ultimate Fighter, with Michael Bisping coaching the opposing Team UK.

The reality TV show, which spawned a feud between the two coaches that continued until their fight, aired on Spike TV and premiered on April 1, 2009, with the live finale on June 20, 2009 in Las Vegas.

On July 11, 2009 at UFC 100 at the Mandalay Bay Events Center in Las Vegas, Henderson and Bisping fought, culminating in Henderson becoming the first man to knock Bisping out, doing so in the second round with an overhand right to the jaw as Bisping was circling to Henderson’s right. This win put Henderson back into contention for a title shot at the UFC Middleweight Champion. The knockout punch won Henderson a $100,000 bonus for “Knockout of the Night” and is considered one of the greatest knockouts in the history of the sport.

Dan Henderson signed a four-fight, 16-month deal with Strikeforce on December 5, 2009, after his contract expired with the UFC. Henderson made his Strikeforce debut on April 17, 2010 at Strikeforce on CBS against Jake Shields. He was also eyed for a light heavyweight match against Gegard Mousasi, and expressed interest in eventually fighting Fedor Emelianenko at some point during his contract. Henderson lost his Strikeforce debut to Jake Shields. Despite hurting Shields and knocking him down in the 1st round, Henderson went on to lose by unanimous decision. The majority of the last rounds were spent on the ground where Shields controlled the fight via grappling. (49–46, 49–45, 48–45).

Henderson faced Renato Sobral on December 4, 2010 at Strikeforce: Henderson vs. Babalu. Henderson won the fight via KO at 1:53 of the first round.

Henderson fought Fedor Emelianenko on July 30, 2011 at Strikeforce: Fedor vs. Henderson. Many had speculated that Henderson would meet Fedor at a catch weight, but Strikeforce later confirmed the fight as a heavyweight bout. Henderson said, “Its tough for me to gain weight. I did weightlifting and plenty of eating; I don’t know what else I’m supposed to do. I’m not going to feel outmatched or small in there.” He had to step on the scales weighing at least 206 pounds in order to qualify for the heavyweight division, and weighed in at 207. Fedor weighed in a bit below his normal weight, with the scale reading 223 pounds. Henderson defeated Emelianenko via KO at 4:12 of the 1st round. This was the last fight on Henderson’s Strikeforce contract. Henderson said he would like to re-sign to defend his Strikeforce Light Heavyweight Championship.

Henderson faced Maurício Rua on November 19, 2011 at UFC 139 for his third run in the UFC. He won the bout via unanimous decision. The back and forth action earned both fighters Fight of the Night honors, and was described by many as one of the greatest fights in UFC history.

The bout with Jones was expected to take place on September 1, 2012 at UFC 151. However, Henderson withdrew from the fight citing a knee injury, and the remainder of the fight card was cancelled.

Henderson faced Lyoto Machida on February 23, 2013 at UFC 157. He lost the bout via split decision.

Henderson faced Rashad Evans on June 15, 2013 in the main event at UFC 161. He lost via split decision.

Henderson faced Vitor Belfort in a rematch on November 9, 2013 at UFC Fight Night 32. Henderson defeated Belfort in their first encounter in 2006 at Pride 32 via unanimous decision. He lost the fight via knockout in the first round, marking the first time in his MMA career that he had been stopped due to strikes. The match with Belfort was the last fight of Henderson’s contract with UFC. On January 22, Henderson revealed to UFC Tonight that he signed a new, six-fight contract with the UFC.

In January 2014, a rematch with Maurício Rua was announced to take place on March 23, 2014 at UFC Fight Night 38. Despite losing the first two rounds after being knocked down by Rua, Henderson rallied back in the third round and won the fight via TKO due to punches. The win also earned Henderson his third Fight of the Night bonus and first Performance of the Night bonus.

Making a quick return to the cage, Henderson faced a much larger Daniel Cormier on May 24, 2014 at UFC 173. He lost the fight via submission (technical submission/rear-naked choke) in the third round after being out-wrestled and held down on the bottom for the majority of the fight.

On November 12, 2014, the UFC announced that Henderson would move down to Middleweight to face Gegard Mousasi on January 24, 2015 in the co-main event at UFC on Fox 14. He lost the fight via TKO in the first round.

Henderson faced Tim Boetsch on June 6, 2015 in the main event at UFC Fight Night 68. He won the fight via knockout at 28 seconds of the first round.

A rematch with Lyoto Machida was expected to take place at Middleweight on April 16, 2016 at UFC on Fox 19. However, on April 13, the UFC announced that Machida declared the usage of a banned substance during an out-of-competition sample collection last week. Machida stated that he was unaware that the substance was prohibited both in and out of competition. Therefore, he was removed from the bout and Henderson was re-booked for another event at a later date.

Henderson was quickly rescheduled to face Hector Lombard on June 4, 2016 at UFC 199. He won the fight via knockout in the second round via a head kick followed by a reverse elbow and earned himself a Performance of the Night bonus, as well as becoming the first fighter to knock Lombard out cold.

Henderson faced then UFC Middleweight Champion Michael Bisping, in a rematch on October 8, 2016 at UFC 204. Despite dropping and nearly finishing Bisping in both the first and second round, he wound up losing the back and forth fight via unanimous decision. Both fighters were awarded Fight of the Night for their performance. At the conclusion of the fight, Henderson confirmed his intention to retire from fighting.

Dan Henderson was inducted into the Fight Wing of the UFC Hall of Fame at the UFC Fan Expo on July 5, 2018, alongside Maurício Rua, for their fight in 2011, which Henderson won by Unanimous Decision (48-47 x3).