A highly regarded grappler on the world stage, Souza is a former Strikeforce Middleweight Champion, and has also formerly competed for DREAM and Jungle Fight.

After this event, Souza's mother moved him to Manaus to go and live with his brother and he started training in Judo and Brazilian jiu-jitsu when he was 17.

Along with Roger Gracie and Marcelo Garcia, Souza is widely considered to be among the greatest BJJ practitioners of his time.

Souza made his mixed martial arts debut on September 9, 2003, at Jungle Fight's inaugural event where he lost to Jorge "Macaco" Patino by KO at 3:13 into the first round.

He returned to mixed martial arts eight months later at Jungle Fight 2 securing a submission win over Victor Babkir under a minute into the first round.

In 2006, Souza fought and drew with UFC Hall of Famer Randy Couture in a grappling contest.

The fight went the distance with Souza continuously going for submissions with Miller escaping multiple rear-naked choke, leglock and armbar-attempts while mounting his own offense on the feet.

Souza was awarded a unanimous decision victory which secured him a place in the semi-final of the Middleweight Grand-Prix.

[10] In the semi-finals which took place at DREAM 6 on September 23, Souza defeated Zelg Galesic early in the first round by armbar submission.

The victory earned him a place in the finals of the tournament and a shot at the DREAM Middleweight Championship against Gegard Mousasi that same night.

In the fight Souza was knocked out early in the first round by an upkick as he attempted to dive past Mousasi's guard to land a strike of his own.

After participating in the tournament, Souza left Xtreme Couture and went to San Diego to train with Saulo and Xande Ribeiro, before leaving to train with Anderson Silva and André Galvão in preparation for Silva's upcoming bout with Thales Leites at UFC 97 at Black House.

[14] In his second defense, Souza lost his Middleweight Championship against American Kickboxing Academy fighter Luke Rockhold via unanimous decision (50–45, 48–47, and 48–47).

[17] On March 3, 2012, Souza made his sixth Strikeforce appearance against late replacement Bristol Marunde.

[21] Philippou pulled out of the bout in early May, citing a cut above his eye, and was replaced by Chris Camozzi.

[25] Souza beat Francis Carmont by unanimous decision (29–28, 29–28, and 30–27) on February 15, 2014, at UFC Fight Night 36.

[33] Romero pulled out of the fight a week before the event, citing a ligament and meniscus tear in his knee.

[40][41] Souza was expected to face Luke Rockhold in a rematch on November 27, 2016, at UFC Fight Night 101.

[56] However, on October 19, 2018, It was reported that Souza replaced injured Luke Rockhold to face Chris Weidman in the event.

[62] Souza remained on the card and faced Jack Hermansson in the main event at UFC Fight Night: Jacaré vs.

[64] Souza moved up to the Light Heavyweight division and faced Jan Błachowicz on November 16, 2019, at UFC Fight Night 164.