After a one-season stint with the 7-Up Uncolas in the PBA, Santos began appearing in serious movie supporting roles in the 1970s. His debut movie was Bontoc with the late action King Fernando Poe, Jr., and his other movies including Little Christmas Tree. In the 1980s he turned to comedy, and became a regular in the Philippine television series Iskul Bukol and T.O.D.A.S.: Television's Outrageously Delightful All-Star Show. He also became a regular host in the noon-time television variety show Eat Bulaga! until 2022. Since then, he starred as lead comic actor in such feature films as I Love You 3X a Day, Bondying (a remake), Wooly Booly, and Humanap Ka ng Panget.
In 2011, Santos played a supporting role alongside Vice Ganda in The Unkabogable Praybeyt Benjamin, which gained the distinction of being the highest-grossing Filipino film of all time.
In 2013, he returned to action via Bang Bang Alley with co-star Megan Young.
In 2015, Santos returned to comedy via the film The Illegal Wife with co-stars Zanjoe Marudo and Pokwang.
Santos's most recent film is TOL in 2019 with co-stars Enchong Dee and Jessy Mendiola.