2000–2019: Further critical and commercial success
Between 2000 and 2010, De Leon only appeared in ten films and ventured further into television. In 2000, he hosted the Filipino edition of the game show Who Wants to Be a Millionaire? Veronique del Rosario-Corpus, Viva Television president, revealed that he underwent training and workshops to prepare for his first hosting stint. He later received a nomination for Best Game Show Host at the PMPC Star Awards for Television. The following year, De León starred with an ensemble cast in Laurice Guillen's American Adobo, which premiered at the San Diego Asian Film Festival. In 2002, he starred in the romantic drama series Ang Iibigin ay Ikaw as well as its sequel, Ang Iibigin ay Ikaw Pa Rin (2003). The same year, he appeared with Vilma Santos in the film adaptation of Lualhati Bautista's novel Dekada '70, under the direction of Chito Roño. The film premiered at the 28th Metro Manila Film Festival, with his performance earning him Best Actor nominations from Gawad Urian and Luna.
In 2003, de Leon starred in the romance film Pangarap Ko ang Ibigin Ka, in which he was paired once again with singer Regine Velasquez; the film was originally planned to be directed by Yam Laranas, but Louie Ignacio was ultimately named as its director. In the same year, De Leon starred in the drama film Mano Po 2: My Home, and he appeared in the 2004 sequel, Mano Po III: My Love, as a different character. In 2004, De Leon was among the council in the second season of StarStruck. He also appeared in the drama series Hanggang Kailan. In 2005, he had a role in the third installment of Now and Forever, Agos. The same year, he was an antagonist in the superhero television series Darna.
In 2006, De Leon played the role of a banking magnate in the romantic family drama Maging Sino Ka Man and later reprised his role in the sequel, Maging Sino Ka Man: Ang Pagbabalik, which aired in 2007. He next starred with an ensemble cast in Joel Lamangan's Blue Moon. De Leon then appeared in the pilot episode of the drama series Pangarap na Bituin, followed by a supporting role in Kahit Isang Saglit (2008). De Leon also starred opposite Angel Aquino in Eddie Romero's final directorial effort, Faces of Love (2007). In 2009, he had supporting roles in the drama series Lovers in Paris and Sana Ngayong Pasko. Later that year, De Leon appeared in the film Mano Po 6: A Mother's Love, which premiered at the 35th Metro Manila Film Festival.
In 2010, De Leon starred with an ensemble cast in Laurice Guillen's Sa 'yo Lamang. The film earned him a Best Actor nomination at the 29th Luna Awards. Also in 2010, he played the character of a black sorcerer in the fantasy film Ilumina. He next appeared in the anthologies SRO Cinemaserye and Maalaala Mo Kaya, as well as making guest appearances in the dramas Jillian: Namamasko Po and Panday Kids. In 2011, De Leon starred in the political drama Sa Ngalan ng Ina and made guest appearances in the dramas 100 Days to Heaven and Bantatay. He also played a supporting role in the fantasy action series Captain Barbell. The same year, he played a special role in the romantic comedy Catch Me, I'm in Love. In 2012, De Leon portrayed General Antonio Luna in the biographical film El Presidente. His performance received a Best Supporting Actor nomination at the 38th Metro Manila Film Festival. 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. In 2013, he produced the play Lorenzo, a musical on the life of Lorenzo Ruiz, with music by Ryan Cayabyab and book and lyrics by Juan Ekis and Paul Dumol. The play's maiden run was held in September 2013 at DLS-CSB's SDA Theater.
De Leon had more supporting roles in soap operas in the succeeding years. He was cast in main roles in several television series, such as Muling Buksan ang Puso (2013), The Legal Wife (2014), Ikaw Lamang (2014), and Beautiful Strangers (2015), earning Best Drama Supporting Actor nominations at the Star Awards for TV for the latter three. In that span, De Leon was in two films, including the action feature Sa Ngalan ng Ama, Ina at mga Anak (2014) and the supernatural horror Tragic Theater (2015). In 2016, he made guest appearances in Ang Probinsyano and Alyas Robin Hood as well as landing supporting roles in Little Nanay and Ang Panday. That same year, he played an ex-military officer-turned-kidnapper in the suspense thriller Dukot. Supporting roles came in the following years, with Kambal, Karibal (2017) and Sana Dalawa ang Puso (2018). In that span, he also made film appearances in Carlo J. Caparas' Kamandag ng Droga (2017), Raya Martin's Smaller and Smaller Circles (2017), and Ruel Bayani's Kasal (2018).
