Her starring roles in the drama series Esperanza (1998), Sa Puso Ko Iingatan Ka (2001), and Basta't Kasama Kita (2003) established her as a leading actress on primetime television.

She received critical acclaim for her role as a woman with dissociative identity disorder in the psychological drama Sabel (2004), for which she won a Gawad Urian and Golden Screen Award for Best Actress.

Santos co-produced the independent drama Ploning (2008) and starred in Mindanao (2019), which were the Philippine submissions for Best International Feature Film at the 81st and 93rd Academy Awards, respectively.

[1][3] Santos and her siblings remained in the Philippines and lived with their nanny, Sabina "Binay" Quinatana, with whom she was close growing up,[5][1][6] and moved to Quezon City where she attended elementary and high school.

[6] At the age of eight, Santos began her professional acting career when she made her debut by portraying a minor role in the television series Kaming Mga Ulila (1986).

[7] Her career prospects improved when she was cast by director Argel Joseph, with whom she worked with in Kaming Mga Ulila, to play the eponymous character in the children's television series Ula, Ang Batang Gubat (1988).

[15] That year, she starred in the teen series Gimik (1996) as part of an ensemble cast that included Marvin Agustin, Mylene Dizon, Diether Ocampo, and G.

[29][30] That same year, she appeared in the police procedural series Basta't Kasama Kita opposite Robin Padilla as a lawyer who gives up on her career to enlist as a National Bureau of Investigation (NBI) agent,[31] which she found a "welcome change" from soap operas.

Joel Lamangan cast Santos as a woman with dissociative identity disorder in the psychological drama Sabel (2004),[34][35] whose script she found risky but necessary for artistic growth.

[37] Johven Velasco from The Manila Times praised Santos for challenging traditional gender roles of women and called the film the "turning point of her career".

[43][44] Santos said in regards to her decision to take up adult roles, "It was part of [my] desire to mature as an actor, to grow, and to establish my identity and versatility in the public's mind.

"[44] Reviews of the film were mixed: Gibbs Cadiz from the Philippine Daily Inquirer criticized its "narrative incoherence and shockingly flippant grasp of history",[45] but Rina Jimenez-David commended Santos for leaving her comfort zone with her role in Sabel.

[50] Critic Nestor Torre Jr. wrote that Santos gave a "gutsy and felt performance",[50] while Asilo praised her "honest-to-goodness portrayal", and said the film "strikes the appropriate emotional tone even as they juggle comedy and light drama".

[56] The film was met with mixed reviews; Philip Cu-Unjieng of The Philippine Star wrote, "There is nothing earth-shaking in the treatment of the material or the performances he [Lee] elicits from the ensemble.

The response from critics was overwhelmingly negative; the Philippine Daily Inquirer's Nestor Torre Jr. dismissed the film for its "thrice-told plots and exhausted stellar performances",[58] while Asilo stated that it "meanders into a list of issues that eventually clutter up its exposition and focus".

[61][62] Jimenez-David wrote that her performance showed "maturity and ripeness, a depth of character that hints at a life lived fully and well", and described the film as "moving, dazzling, and yet intimate and comforting".

[67] Santos's next role in 2008 was in Jun Lana's psychological horror thriller Mag-ingat Ka Sa... Kulam as a woman who questions her own sanity after a car accident leaves her with amnesia.

[76] In 2012, Santos collaborated with Javier Reyes in Mga Mumunting Lihim with Iza Calzado, Janice de Belen, and Agot Isidro.

[82][83] Nestor Torre Jr. from the Philippine Daily Inquirer dismissed her performance as "too melodramatically achieved, and at times [Santos's] assumption of vengeful power ... was too easily pulled off", concluding that the "key thematic intention of female empowerment wasn't sufficiently earned on a realistic level".

[84] In 2014, Santos was cast in the supernatural horror T'yanak, an abridged retelling of Lore Reyes and Peque Gallaga's 1988 film of the same name, in which she played an adoptive mother to a demonic infant.

"[100] SunStar Davao felt that the film lacked "depth and cultural nuance" and criticized Mendoza's misrepresentation and unfamiliarity of the region's ethnic groups.

[101] In contrast, Jessica Kiang from Variety highlighted Santos's "de-glammed, gently anguished, remarkably sympathetic performance", and called the film "well acted but clumsy".

These will be a biopic of Regal Entertainment founder Lily Monteverde, and a remake of the French comedy series Call My Agent!, which co-stars Edu Manzano, Gina Alajar, and RK Bagatsing.

[110] Santos is also attached to star as a fictional Philippine President who is the target of an assassination plot in the upcoming eight-part crime thriller miniseries The Bagman.

[115] She is noted for playing in a range of material,[116] including indie films,[117] and Brillante Mendoza, who directed Santos in Mindanao, praised her versatility.

[2] Journalist Rose Fausto wrote that she "possesses an advanced skill in crying and acting out emotions effectively in dramatic scenes because she has a wealth of experience to draw from".

[116] Commenting on her comedic performances, Asilo praised her ability to "get off the beaten track", and called it a "brave and bold decision that evinces growth and maturity".

[122] "Making people laugh is a special skill that requires an idiosyncratic combination of innate talent and time-honed experience", he says, "but [Santos's] spot-on characterization and lived-in earnestness manage to see her through".

[123] Dennis Trillo, her co-star in Aishite Imasu 1941: Mahal Kita and Mag-ingat Ka Sa... Kulam, considers Santos to be "the picture of excellence in the profession",[124] and Iza Calzado, with whom she worked with in Ouija and Mga Mumunting Lihim, believes that she is a "naturally gifted" actress and her "eyes alone express emotions".

[130] It was described by Ruel De Vera of the Philippine Daily Inquirer as "recipes ranging from interesting comfort food to more complicated dishes", and added that "[i]t doesn't simply present itself as a book for would-be cooks.