In spite of his amateur pedigree, Sakuraba was forced to work his way up from the bottom of the UWFi’s rung, as it is traditional in puroresu. Sakuraba lost his debut on August 13, 1993 to Steve Nelson and went winless through his rookie year with the league. It is also popularly alleged that under the eye of Kiyoshi Tamura, he was made to perfectly perform menial chores about the dojo. Still undeterred, Sakuraba steadily built a working knowledge of submission holds upon his freestyle wrestling base until his efforts were at last rewarded with a win over Mark Silver in October 1994.

Though his record remained below .500, Sakuraba continued to edge his way closer to mid-card status through the rest of the year. Then, in 1995, the UWFi began an interpromotional feud with New Japan Pro-Wrestling. The vast majority of UWF-i workers came out on the losing end of the booking to the larger and more mainstream promotion and Sakuraba was no exception. He was defeated in high-profile bouts to Tokimitsu Ishizawa, Koji Kanemoto and Shinjiro Otani, bringing Sakuraba a new level of exposure to the public. The ring psychology and technical prowess he displayed in the bouts also impressed the management of the UWF-i enough that he was finally pushed towards main event status.

New Japan’s dominance in the feud injured the marketability of the UWFi promotion, which had pressed the perception that their athletes boasted legitimate skill in real fighting. In a bid to regain credibility, Yoji Anjoh travelled to California to perform a dojo challenge on Rickson Gracie, only to be swiftly and brutally defeated before the assembled Japanese press that had followed him there. With the UWFi’s formerly fearsome reputation in tatters, its attendance numbers swiftly decreased, with the federation closing its doors once and for all in December 1996. In their final show it was Sakuraba who at long last headlined, defeating Anjoh by submission.

Though sources often cite Sakuraba’s match with Kimo Leopoldo on July 14, 1996 as his first experience with mixed martial arts, there is debate about whether it was a shoot or a worked match. Sakuraba himself has stated that he doesn’t remember it. However, his first contact with MMA can be traced to his different style fight at 26 June 1996 against Dutch kickboxer Rene Rooze, which was won by Sakuraba via ankle hold.

With Nobuhiko Takada having left Kingdom to challenge Rickson Gracie in an event called Pride Fighting Championships, the still struggling promotion capitalized on Sakuraba’s newly found popularity establishing him as Kingdom’s top talent. He embarked on a winning streak against several foreign mixed martial arts competitors including Paul Herrera, Rene Rooze, Mark Hall and Orlando Weit. However, Kingdom continued to flounder and finally folded in March 1998.

While the Japanese fight media rejoiced and elevated Sakuraba to superstar status, the Gracie family took great umbrage over the incident, feeling that they had been cheated by Pride. Despite Sakuraba challenging Royler’s older brother Rickson Gracie after the match, it was his younger brother and former UFC Champion Royce Gracie who, compelled to set the record straight and re-assert the dominance of his family, returned to the sport of mixed martial arts in 2000 and entered the 16-Man Pride Grand Prix alongside Sakuraba and several other top fighters of the era. Placed on the same side of the bracket, a special set of rules were requested by the Gracies in the event of a Sakuraba-Royce match, including no referee stoppages and no time-limits, the fight ending only in the event of a submission or knock-out (something prohibited in modern MMA because of the widely adopted Unified Rules of Mixed Martial Arts limiting matches to 25 minutes overall, 5 x 5 minute rounds).

After a quick TKO victory over decorated judoka Yoon Dong-Sik in the opening round, Sakuraba suffered a particularly devastating yet controversial loss against Ricardo Arona in the quarterfinal of the tournament in June 2005. Although Sakuraba put Arona on his back and seemed to put to work his signature jumping stomps, the heavier and stronger Arona soon overpowered him, landing a series of brutal knees to the head, as well as hard soccer kicks to the face. The Brazilian’s toenail accidentally slashed open the skin over Sakuraba’s left eye, which Ricardo then capitalized on by squeezing the cut and digging his finger into it in order to force the doctor stoppage. The Japanese tried to keep on, but Arona hit another flurry of knees to the head, and ended the fight landing soccer kick after soccer kick, rendering Kazushi’s face severely swollen and bloody. Arona won by unanimous decision.

On 3 May 2006, Sakuraba surprisingly appeared with Hero’s head Akira Maeda at a Hero’s event wearing his street clothes (yellow shirt and blue jeans) and a pro wrestling mask in the style of one of his childhood heroes, Tiger Mask. He did not reveal himself, but it was apparent that it was a masked Sakuraba and that he signed with K-1 and FEG. A day later, Sakuraba appeared at a FEG press conference to announce he would fight in Hero’s. His defection to Hero’s was a culmination of several signs that suggested he was leaving Pride. It was reported that Sakuraba left Takada Dojo (run by Pride’s general manager, Nobuhiko Takada), and conspicuously was not entered into Pride’s 2006 Open Weight Grand Prix Tournament.

In spite of this revelation, rather than being granted a break to recover and possibly undergo surgery Sakuraba scheduled to return to action on December 31, 2006 against Yoshihiro Akiyama at K-1 Dynamite!!. During the bout, Sakuraba was hit with several punches and he rushed to get the takedown, but in doing so he slipped from Akiyama’s body. As the sequence repeated itself over and over while Sakuraba took punishment, he opted to drop to his back and attempt a kneebar from there, but his grip on the judoka inexplicably failed again. Having Sakuraba trapped against the ropes and struggling for his submission, Akiyama was free to attack with ground and pound for the referee stoppage. Words were exchanged between Sakuraba and referee Yoshinori Umeki prior to the stop, which was brought on by the sounding of a bell at the behest of Akira Maeda, the event coordinator, the referee separating the fighters following the bell rather than initiating the stop himself.

On 2 June 2007, Sakuraba rematched Royce Gracie in K-1 Dynamite!! USA. While Sakuraba knocked Gracie to the canvas in the opening seconds, the bout itself was fought at a relatively slow pace, with Kazushi scoring multiple takedowns and Gracie scoring a number of flailing kicks to the legs and face from the bottom, as well as standing knee strikes to Kazushi’s injured and bandaged knee. The Japanese wrestler also besieged Gracie on the ground, finishing the bout having taken the back of Gracie and searching for an armbar. Royce won by unanimous decision, which many viewers and MMA sites disputed immediately on the feeling that Sakuraba won the fight. Sherdog scored it 29–28 in favor of the Japanese fighter. Moreover, Gracie tested positive for steroids after the bout.

Sakuraba returned to the ring on 17 September 2007 at K-1 Hero’s 10 against former NJPW pro wrestler Katsuyori Shibata. Prior to the bout, Shibata’s trainer, Masakatsu Funaki had challenged Sakuraba on the basis that he their styles would make for an entertaining contest. Shibata came out striking aggressively, but was soon taken to the canvas by Sakuraba’s trademark single leg. Shibata unleashed a torrent of blows off his back, but the more experienced Sakuraba responded with strikes of his own before transitioning into an armbar and finishing the bout.

In 2008, it was announced that Kazushi Sakuraba would compete in the Middleweight Grand Prix of the new MMA promotion, Dream. On 29 April 2008, Sakuraba defeated Andrews Nakahara in the main event at Dream 2: Middle Weight Grandprix 2008 1st Round. However, he was knocked out (and thus eliminated from the tournament) by Melvin Manhoef in the main event of Dream 4: Middle Weight Grandprix 2008 2nd Round. During the match, Sakuraba suffered an ulnar fracture of the left forearm, which was caused by a kick from Manhoef./

Sakuraba fought for the Dream Welterweight Championship against current champion Marius Zaromskis at Dynamite!! 2010 in December 2010. The fight ended in doctor stoppage, Sakuraba’s ear was partially ripped off.

On August 12, 2012, Sakuraba, alongside Katsuyori Shibata, started appearing in New Japan Pro-Wrestling. It was Sakuraba’s first work for the company since 1995, and the first ever as a free agent instead of a representative from another promotion. Sakuraba and Shibata wrestled their first match on September 23, defeating Hiromu Takahashi and Wataru Inoue in a tag team match. Sakuraba and Shibata, collectively dubbed Laughter7, continued their winning ways at the following two pay-per-views, King of Pro-Wrestling on October 8 and Power Struggle on November 11, both times defeating the team of Togi Makabe and Wataru Inoue. Also at Power Struggle, Shinsuke Nakamura nominated Sakuraba as the next challenger for his IWGP Intercontinental Championship. On December 2, Sakuraba won his first exchange with Nakamura, when Laughter7 defeated Nakamura and Tomohiro Ishii in a tag team match to remain undefeated since their return. On January 4, 2013, at Wrestle Kingdom 7 in Tokyo Dome, Sakuraba suffered his first defeat since his return to professional wrestling, when he unsuccessfully challenged Shinsuke Nakamura for the IWGP Intercontinental Championship. Sakuraba and Shibata returned to their winning ways at the following pay-per-view, The New Beginning on February 10, where they defeated Hirooki Goto and Wataru Inoue in a tag team match. On April 7 at Invasion Attack, Sakuraba and Shibata suffered their first tag team loss, when they were defeated by Hirooki Goto and Yuji Nagata via referee stoppage, when Sakuraba injured his right elbow, after taking a belly-to-back suplex from Nagata, and unable to continue the match. New Japan later announced that Sakuraba would be sidelined for two to three months. Sakuraba wrestled his return match on July 20, defeating Yuji Nagata via submission. On September 8, Sakuraba and Shibata took part in the Wrestle-1 promotion’s inaugural event, defeating Masakatsu Funaki and Masayuki Kono in a tag team match. Sakuraba continued his rivalry with Yuji Nagata at the September 29 Destruction pay-per-view, where he and Shibata defeated Nagata and Manabu Nakanishi with Sakuraba pinning his rival for the win.

On October 14, Sakuraba was defeated by Nagata in a singles rematch between the two. Following the match, Sakuraba and Nagata came together to accept a challenge issued by Daniel and Rolles Gracie On January 4, 2014, at Wrestle Kingdom 8 in Tokyo Dome, Sakuraba and Nagata defeated the Gracies via disqualification, after Nagata was choked out with a gi. A rematch between the two teams took place on February 11 at The New Beginning in Osaka and saw Rolles submit Sakuraba for the win. Sakuraba suffered another loss against the Gracies on May 3 at Wrestling Dontaku 2014, where he teamed with Shinsuke Nakamura. On May 25 at Back to the Yokohama Arena, Sakuraba ended the Gracies’ win streak by defeating Rolles in a singles match. Sakuraba then started a new rivalry with Minoru Suzuki, while also forming a partnership with Toru Yano, who was also involved in his own rivalry with Suzuki’s Suzuki-gun stable. The partnership led to Sakuraba becoming an associate of Yano and Nakamura’s Chaos stable, eventually becoming a full-time member. The rivalry between Sakuraba and Suzuki culminated in a match on January 4, 2015, at Wrestle Kingdom 9 in Tokyo Dome, where Sakuraba was defeated.

On November 22, 2014, Sakuraba fought Renzo Gracie in a grappling match in Metamoris V. Renzo played defensive closed guard earlier in the match, with the two exchanging guillotine choke attempts, but he eventually flipped Sakuraba over and pinned him. However, Sakuraba resisted all of his submission attempts, and with 90 seconds left he scrambled and tried to lock a Kimura, which was unsuccessful. The fight ended in a draw.

On October 8, 2015, new Japanese mixed martial arts promotion Rizin Fighting Federation announced at a press conference that Sakuraba would face fellow Japanese fighter and grappler Shinya Aoki on the December 29, 2015. This was Sakuraba’s first fight after taking four years away from the sport. Sakuraba lost the fight via TKO at 5:56 in the first round, after being taken down and receiving ground and pound.

On October 15, 2017, Sakuraba fought former UFC champion Frank Shamrock at RIZIN fighting world grand Prix 2017 Autumn: Aki Jin event in Fukuoka, Japan for a grappling exhibition march at 84 kg division. The match ended with a draw decision.

In April 2018, Sakuraba announced the formation of a submission wrestling promotion named Quintet (grappling). Based on five-man teams, it is fought under a kachi-nuki-shiai tournament format similar to Nanatei Judo. He competed in the inaugural event, but his team was eliminated in the semi-final round.