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Santos faced Jan Błachowicz on February 23, 2019, at UFC Fight Night 145. He won the fight by TKO in the third round. This win earned him the Performance of the Night award.

After going undefeated at 3–0 in Light Heavyweight bouts, Santos challenged Jon Jones for the UFC Light Heavyweight Championship in the main event at UFC 239 on July 6, 2019. He lost the back-and-forth fight via split decision. Despite the loss, Santos was the first fighter in MMA history to win a judge's scorecard against Jones. During the fight he sustained a torn left LCL, PCL, MCL, meniscus and cracked Tibia along with a partially torn right ACL.

Santos faced Anthony Smith on February 3, 2018, at UFC Fight Night 125. He won the fight via technical knockout in round two. This win earned him the Fight of the Night bonus.

Santos faced David Branch on April 21, 2018, at UFC Fight Night 128. He lost the fight via knockout in round one.

Santos faced promotional newcomer Kevin Holland on August 4, 2018, at UFC 227. He won the fight by unanimous decision (29–27, 29–27, and 29–26).

Santos was scheduled to face Jimi Manuwa in a light heavyweight bout on September 22, 2018, at UFC Fight Night 137, replacing injured Glover Teixeira. Manuwa would also pull out of the bout on September 16, 2018 due to a torn hamstring and he was replaced by Eryk Anders. Santos defeated Anders via referee stoppage TKO when Anders failed to make it to his corner at the conclusion of round three. This win earned him the Fight of the Night award.

Santos faced Jimi Manuwa on December 8, 2018, at UFC 231. He won by KO on early 2nd round. This win earned him the Performance of the Night award and tied for most bout in a calendar year with 5.

Santos faced Jack Marshman on February 19, 2017, at UFC Fight Night 105. He won the fight via TKO in the second round due to a combination of a spinning heel kick and punches and picked up a Performance of the Night bonus award.

Santos faced Gerald Meerschaert on July 8, 2017, at UFC 213. He won the fight via TKO in the second round.

Santos was briefly linked to a bout with promotional newcomer Michał Materla on October 21, 2017, at UFC Fight Night 118. However, it was revealed on 1 September that Materla had reneged on his agreement with the UFC and was re-signing with the Polish regional promotion KSW. In turn, Santos was removed from the card and faced Jack Hermansson a week later at UFC Fight Night 119. He won the fight via technical knock out in round one.

Santos faced Nate Marquardt on May 14, 2016, at UFC 198. He won the fight via knockout in the first round.

Santos fought Gegard Mousasi on July 9, 2016, at UFC 200, filling in for an injured Derek Brunson. He lost the fight via knockout in the first round.

Santos fought Eric Spicely on September 24, 2016, at UFC Fight Night 95. In a large upset, he lost the fight by submission in the first round.

Santos next faced Andy Enz on January 30, 2015, at UFC 183. He won the fight via TKO in the first round.

Santos faced promotional newcomer Steve Bossé on June 27, 2015, at UFC Fight Night 70. He won the fight by knockout in the first round and earned a Performance of the Night bonus.

Santos faced Elias Theodorou on December 10, 2015, at UFC Fight Night 80. He won the fight by unanimous decision (29–28, 29–27, and 29–27).

For his second fight with the promotion, Santos faced Ronny Markes on March 23, 2014, at UFC Fight Night: Shogun vs. Henderson 2. He won the fight via TKO in the first round.

In March 2013, it was announced that Santos was part of the cast of The Ultimate Fighter: Brazil 2.

Despite not winning the show, Santos was signed to a contract by the UFC. He made his debut on August 3, 2013, at UFC 163 against The Ultimate Fighter: Brazil winner Cezar Ferreira. He lost the fight via submission in the first round.

Santos was born into a poverty-stricken family in Rio de Janeiro. In the early childhood, he suffered of an undiagnosed disease that spawned growing cysts in his stomach, which were surgically removed. In one of the occasional floods in his city, Santos' family lost their belongings and after a period of homelessness they settled in the notorious neighborhood of Cidade de Deus. Santos' father died just days after his mixed martial arts debut in 2010.

He made his professional MMA debut in October 2010. Before joining The Ultimate Fighter, he had a record of 8 wins and only 1 loss.

Thiago Santos de Lima (born January 7, 1984) is a Brazilian mixed martial artist currently competing in the light heavyweight division of the Ultimate Fighting Championship. A professional competitor since 2010, he gained entrance into the UFC by competing on The Ultimate Fighter: Brazil 2. As of February 10, 2020, he is #2 in the UFC Light Heavyweight rankings.