De Leon began his career as a teenager, winning the FAMAS Award for Best Actor for his screen debut in Lino Brocka's Tinimbang Ka Ngunit Kulang (1974).

He gained wider recognition for his portrayal of a naive peasant in Eddie Romero's Ganito Kami Noon... Paano Kayo Ngayon?

De Leon continued to gain recognition and critical acclaim for his film work in the 1980s, 1990s, and 2000s, with leading roles in Haplos (1982), Imortal (1989), Biktima, My Other Woman (both in 1990), Ipagpatawad Mo (1991), Gaano Kita Kamahal (1993), Madrasta (1996), Nasaan ang Puso (1997), Bulaklak ng Maynila (1999), Dekada '70 (2002), Mano Po III: My Love (2004) and Magkaibigan (2008).

[8] At age 17, De Leon made his acting debut in Lino Brocka's 1974 film Tinimbang Ka Ngunit Kulang.

He portrayed a naive Indio in Eddie Romero's period drama Ganito Kami Noon... Paano Kayo Ngayon?.

[13] He subsequently played a Japanese-Filipino military officer in Mario O'Hara's period drama Tatlong Taong Walang Diyos.

He co-starred with Vilma Santos and Mat Ranillo III in Elwood Perez' Masarap, Masakit ang Umibig, which earned him a Best Actor nomination at the 25th FAMAS Awards.

[15] He then appeared in Mike De Leon's coming-of-age Kung Mangarap Ka't Magising, which premiered at the third Metro Manila Film Festival.

[20] The same year, he appeared in two more production: the drama Taga sa Panahon, which premiered at the sixth Metro Manila Film Festival,[21] and Aguila.

De Leon had three releases in 1982: Ishmael Bernal's Relasyon,[24] for which he won Best Actor at the Catholic Mass Media Awards as well as another nomination at the FAMAS Awards;[25][26] the mystery drama Haplos,[27] for which he received his second Best Actor win at the Metro Manila Film Festival; and finally, Lino Brocka's thriller drama Cain at Abel.

[35] In 1987, he appeared in Lino Brocka's Maging Akin Ka Lamang,[36] which earned him his fourteenth Best Actor nomination at the FAMAS Awards.

[41] For the final year of the decade, De Leon starred in two productions, including the third segment of the anthology film 3 Mukha ng Pag-ibig and[42] Eddie Garcia's Imortal.

[43] He won his third Best Actor trophy at the Metro Manila Film Festival and received nominations from FAMAS and Gawad Urian in the same category.

[48][49] He also appeared in the romantic drama My Other Woman,[50] for which he won Best Actor at the FAMAS, Gawad Urian, and Catholic Mass Media Awards.

[54][55] In 1992, De Leon starred in Joel Lamangan's Hiram na Mukha, followed by the biopic Gaano Kita Kamahal a year later.

His portrayal earned him Best Actor wins at Luna and the Metro Manila Film Festival, as well as nominations from Gawad Urian and the Young Critics Circle.

[67] Veronique del Rosario-Corpus, Viva TV president, revealed that he underwent training and workshops to prepare for his first hosting stint.

The following year, De Leon starred with an ensemble cast in Laurice Guillen's American Adobo, which premiered at the San Diego Asian Film Festival.

[78] De Leon then appeared in the pilot episode of the drama series Pangarap na Bituin,[79] followed by a supporting role in Kahit Isang Saglit (2008).

[80][81] De Leon also starred opposite Angel Aquino in Eddie Romero's final directorial effort, Faces of Love (2007).

[citation needed] Also in 2012, he played supporting roles in the dramas Dahil sa Pag-ibig, Pahiram ng Sandali, Kung Ako'y Iiwan Mo, and Luna Blanca.

He was cast in main roles in several television series, such as Muling Buksan ang Puso (2013),[94] The Legal Wife (2014),[95] Ikaw Lamang (2014),[96] and Beautiful Strangers (2015),[97] earning Best Drama Supporting Actor nominations at the Star Awards for TV for the latter three.

[citation needed] In that span, De Leon appeared in two films, including the action feature Sa Ngalan ng Ama, Ina at mga Anak (2014)[98] and the supernatural horror Tragic Theater (2015).

[112] In 2023, De Leon reprised his role in the psychological thriller Cattleya Killer, the sequel to the 1996 film Sa Aking mga Kamay.

[113] Also in 2023, De Leon was cast as the main antagonist in the action drama series Batang Quiapo, based on the 1986 action-comedy film of the same name.

He was supposed to be the running mate of incumbent vice governor Ricky Recto but instead ran with former Batangas police director Nestor Sanares;[116] he lost to Mark Leviste.

[120] In a 2001 interview with journalist Remy Umerez, Cesar Montano described De Leon as the most professional actor he had ever worked with, saying: "He comes to the set fully prepared and you better watch out if you don't know your lines well.

[122] In 2007, the Philippine Entertainment Portal named three films, Aguila (1979), Dekada '70 (2002), and Ganito Kami Noon... Paano Kayo Ngayon?

De Leon has been inducted into the hall of fame of two major Philippine award-giving bodies: FAMAS (1993) and the Metro Manila Film Festival (2019), in the Best Actor category.

[137] With more than 200 acting credits to his name, some of De Leon's most critically and commercially successful films, according to the review aggregator site Rotten Tomatoes include Tinimbang Ka Ngunit Kulang (1974), Ganito Kami Noon... Paano Kayo Ngayon?