After a one-season stint with the 7-Up Uncolas in the PBA, Santos began appearing in serious movie supporting roles in the 1970s.

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.

[6][7] In 2014, Santos returned to comedy via the film My Illegal Wife with co-stars Zanjoe Marudo and Pokwang.

In 2021, Santos started a YouTube channel under the name "Jimmy Saints" where he covers vignettes about his life.