She made her film debut in Peque Gallaga's horror anthology Shake, Rattle & Roll III (1991) and was cast in small and uncredited roles throughout the 1990s and 2000s.

[7] Her mother, Rosie de Leon, was a homemaker and a professional bowler,[8] who earned a gold medal when the Philippines won the team event at the 1983 Southeast Asian Games.

[13] Her interest in pursuing a career in acting began when she served as a wardrobe supervisor for the stage productions: "I would watch behind in the wings at the backstage and was so amazed at what they were doing and that's when I really fell in love with theater ...

"[6]: 2:31  De Leon's first acting assignment was in a play written by Floy Quintos and directed by Tony Mabesa, portraying a rural laundrywoman.

[6]: 2:58  She considered Mabesa as a mentor who trained her using an "acting-for-dummies style" process, and credits professor Jose Estrella for teaching acting techniques to prepare her for playing roles on film and television.

Her other roles include the protagonist Portia in William Shakespeare's The Merchant of Venice and the dual parts of a nurse and a messenger in the Greek tragedy Medea.

[14][11] De Leon made her film debut as a background actor in Peque Gallaga's horror anthology Shake, Rattle & Roll III (1991), a part she later described as one during which she had "the spotlight for a few seconds".

[16] While struggling to establish her acting career, she worked various jobs, including as a mascot performer, waitress, and cashier to make ends meet.

[16] During the next decade, De Leon appeared predominantly in small and uncredited roles, playing characters which she described as "a device to get the story moving or a sounding board for the lead".

[13] In a 2022 interview with Vanity Fair, she expressed frustration at being typecast into nameless and fleeting parts, though she did not mind this if it led to steady work, remarking, "If I'm going to keep playing the same characters, I might as well have fun with them, not take everything so seriously.

"[17] De Leon's career prospects improved when she was cast in Jerrold Tarog's horror thriller Aswang (2011), playing the mother of Paulo Avelino's character.

[21] The coming-of-age drama Billie and Emma (2018), directed by Samantha Lee, saw De Leon portray a stern principal nun of an all-girls Catholic school.

[22] Lav Diaz's science fiction drama The Halt (2019) featured De Leon as an education minister in a post-apocalyptic Manila, where people are fighting an oppressive regime headed by Joel Lamangan's character.

[36] In Midnight in a Perfect World (2020), a horror thriller about unexplained disappearances caused by rolling blackouts,[37] starring Glaiza de Castro, Jasmine Curtis-Smith, Dino Pastrano, and Anthony Falcon,[38] De Leon played the supporting role of Pastrano's mother, in a performance described by Oquiza as unorthodox and "hard to categorize".

[44] Oquiza took note of how well she "blends comic relief with a commanding presence through bluntness and candor", adding that: "Her true brilliance lies in portraying her character's silent vulnerability, facing the reality of aging and lost beauty.

Drawing from experiences of family members employed within the service industry,[53][50] she stated, "Quiet and unassuming, my loved ones kept ... their heads down, absorbing microaggressions under a layer of agreeableness, their smiles protecting their livelihoods.

[56] De Leon's performance received critical acclaim; Esther Zuckerman of The Hollywood Reporter wrote that she "balances deft comedy, visceral anger and potent sensuality",[47] and Clayton Davis of Variety praised her "utterly lived-in and commanding" portrayal, describing her as an "acting giant" who delivered the "defining supporting performance of the year".

[48] Writing for The Guardian, Ryan Gilbey considered her to be "intensely satisfying" and credited De Leon for playing a "woman who harbors enough experience of injustice and reserves of strength to pounce on power".

Playing the character of a powerful and demanding retail mogul was a departure from De Leon's previous "gritty roles" and an experience she found enjoyable.

[72] Set in Chicago, the film depicts De Leon as a community theater performer who encourages a dejected construction worker (played by Keith Kupferer) to take part in their production of Romeo and Juliet.

The critic Adrian Horton of The Guardian noted how much De Leon's character "blazes in every scene, not missing a single ego-deflating punchline",[73] while The Hollywood Reporter's Jon Frosch found her portrayal of the "bossy, chain-smoking, F-bomb-dropping actress" to have the "right balance of absurdity and pathos".

[75] In Nathan Silver's comedy film Between the Temples, she played an overbearing stepmother to Jason Schwartzman's character, who falls in love with his grade school music teacher.

[80] De Leon will next star, alongside Nicole Kidman, in the second season of the Hulu thriller drama series Nine Perfect Strangers, based on the 2018 novel by Liane Moriarty.

[85] As an actor who made her breakthrough in her 50s, De Leon is an advocate for diversity in roles that older women play on screen, arguing that they should not be typecast to maternal characters.