It is a crossroads fight in some respects, as the 38-year-old Santos is nearly three years removed from an unsuccessful challenge for the UFC's 205-pound title and Ankalaev, 29, is one of the division's rising contenders.
The fights at the UFC Apex will be broadcast Saturday on ESPN+, with the main card starting at 7 p.m. ET and the prelims at 4 p.m.
Santos (22-9) defeated Johnny Walker by unanimous decision in October to bounce back from three straight losses. The skid began with his July 2019 fight against then-champion Jon Jones. Santos is No. 9 in ESPN's light heavyweight rankings.
Ankalaev (16-1) has won seven fights in a row since dropping his UFC debut in 2018. His most recent win was a unanimous decision over Volkan Oezdemir in October. Ankalaev is ranked No. 8 among light heavyweights by ESPN.
How to watch the fights
Stream all of the fights on ESPN+: Download the ESPN App
Don't have ESPN+? Get it here.
There's also FightCenter, which offers live updates for every UFC card.
Saturday fight card
ESPN+, 7 p.m. ET
Light heavyweight: Thiago Santos vs. Magomed Ankalaev
Men's bantamweight: Marlon Moraes vs. Song Yadong
Men's featherweight: Sodiq Yusuff vs. Alex Caceres
Light heavyweight: Khalil Rountree Jr. vs. Karl Roberson
Lightweight: Drew Dober vs. Terrance McKinney
Middleweight: Alex Pereira vs. Bruno Silva
ESPN+, 4 p.m. ET
Welterweight: Matthew Semelsberger vs. AJ Fletcher
Women's flyweight: JJ Aldrich vs. Gillian Robertson
Men's bantamweight: Trevin Jones vs. Javid Basharat
Men's featherweight: Damon Jackson vs. Kamuela Kirk
Women's flyweight: Sabina Mazo vs. Miranda Maverick
Middleweight: Dalcha Lungiambula vs. Cody Brundage
Men's bantamweight: Guido Cannetti vs. Kris Moutinho
Light heavyweight: Tafon Nchukwi vs. Azamat Murzakanov
Ian Parker's best bet
Santos will be looking to make it two in a row if he can stop the hype train known as Ankalaev. This is a nightmare matchup for Santos. The old Santos, I would have given a chance to based on his striking and aggressive demeanor. However, since his double knee surgery, he is a more tentative fighter and doesn't seem to carry that same power in his hands that he once did. And once this fight hits the floor, Santos will be in no man's land and be absolutely dominated by Ankalaev.
For more from Parker on this fight, including how he sees it ending, check out the ESPN+ expert picks and best bets article (see link below), which also will feature analysis by Fight Ready striking coach Eddie Cha and betting expert Reed Kuhn.