Santiago Ponzinibbio began training when he was 13 years old after watching a kickboxing class in Argentina.  He currently holds a purple belt in Brazilian Jiu Jitsu.  Ponzinibbio was a title holder for Champion of the Nitrix (77kg), Champion of the BlackMonster (77Kg), Champion of the São José SuperFight (77Kg), Champion of the GP Insano of MMA (77Kg), and Estate of Santa Catarina Boxe Champion.

Santiago Ponzinibbio competed on the second season of The Ultimate Fighter: Brazil, and was the only non-Brazilian cast member on the show.  He defeated Thiago "Bel" Silva to get into the house and was the second pick of Antônio Rodrigo Nogueira.  He made the quarterfinals by defeating Marcio Santos, and eventually earned $25,000 for his knockout of the season performance.  Ponzinnibio then went on to make the semi-finals by defeating replacement Cleiton Duarte.  In the semi-finals, Ponzinibbio defeated Leonardo Santos in a fight of the season performance, netting both fighters a $25,000 bonus and Ponzinibbio's second bonus of the season.  The fight earned him a spot in the finals against William Macario, but Ponzinibbio suffered a broken hand in the bout which did not heal in time for the live finale.  Instead, it was Santos who replaced him and went on to win The Ultimate Fighter title.

Three months after the TUF Brazil 2 finale, Santiago Ponzinibbio was ready to return to action and made his UFC debut against top welterweight prospect Ryan LaFlare.  LaFlare won the fight via wrestling-heavy decision, upsetting the hype Ponzinibbio had built up on the show.  Following the fight and nearly a year-long lay-off, Ponzinibbio returned to form in securing a quick first round victory over Wendell Oliveira for his first professional UFC win.  Ponzinibbio then went on to face Sean Strickland at UFC Fight Night: Bigfoot vs. Mir, earning a unanimous decision and giving Strickland his first professional loss following a 15-0 record.  Ponzinibbio's win was a part of the fight card's record-breaking 11-straight underdog victories.

The Ultimate Fighter: Brazil 2

Episode 2 Ponzinibbio def. Thiago Silva by TKO (punches) in Round 2
Episode 7 Ponzinibbio def. Marcio Santos by TKO (punches) in Round 1
Episode 11 Ponzinibbio def. Cleiton Duarte by Unanimous Decision
Episode 12 Ponzinibbio def. Leonardo Santos by Unanimous Decision