Both the acting and showbiz industry are not new to Padilla. He comes from a multi-faceted background, which includes talented performers, and a political family. His father Casimero Padilla, Sr., who was a film director, served as vice-governor of Camarines Norte in the 1970s and assemblyman in the 1980s; while his mother was an actress, and three of his siblings Rustom, Rommel, and Royette are actors. His half brother Casimero Roy A. Padilla, Jr. succeeded his father's political endeavors, serving as a union leader, a congressman, and three-term governor of Camarines Norte.
Padilla's movies with Sharon Cuneta in Maging Sino Ka Man, and Vina Morales in Ang Utol Kong Hoodlum series were blockbuster hits. He figured accidents while filming Tulak ng Bibíg, Kabig ng Dibdíb when he was trapped inside a speeding car that flew into the air, flipped and landed on its roof. Padilla's worst accident was when a blasting scene for Utol Kong Hoodlum burned him literally, which left scars around his abdomen and arms.
Padilla crossed over from the silver screen to television through the ABS-CBN comedy show Pwedeng-Pwede. In 2002, he reprised his role as Anghel in the movie "Hari ng Selda: Anak ni Baby Ama 2" with Angelika dela Cruz, a sequel to the 1990 film. The following year, he topbilled his first primetime action-drama series, Basta't Kasama Kita. In 2005, he did two movies: the horror thriller Kulimlim and the comedy "La Visa Loca". He received Best Actor honors in the 2006 Urian Awards.
Padilla had transferred to GMA Network, after his contract with ABS-CBN, where he starred in the TV series Asian Treasures. He has also signed a two-film contract under GMA Network's film outfit GMA Films; first was Till I Met You, the second one was the horror-suspense Sundo.
In 2009, Padilla did Sundo of Viva Films, before, he was opted out of his exclusive contract that allows him do movies for other film outfits including Star Cinema Productions, FLT Films, Millennium Cinema, and GMA Films. On the same year, he also did the title role of "Totoy Bato", which was an adaptation from a novel by Carlo J. Caparas.
In 2010, Padilla returned to ABS-CBN. His projects with the network included the sitcom Toda Max, which was launched in November 2011, this was Padilla's second over-all sitcom his last one with Pwedeng Pwede with his former co-star, the late comedian Redford White.
In the last quarter of 2013, Padilla once again returned to GMA Network, where he starred in Adarna for his cameo role.
In 2015, Padilla will be paired to former Japanese AV Idol Maria Ozawa for Nilalang for the 2015 Metro Manila Film Festival.
On December 1, 2015, he returned to his original mother network, ABS-CBN after 2 years and he became one of the judges in the return of Pilipinas Got Talent for its 5th season this late 2015 to 2016.
Padilla is an anti-malaria advocate since 2004; he appealed for media support for his cause against the disease in the press briefing of Department of Health's 'Movement Against Malaria'. As a MAM spokesperson, he engaged television networks in the campaign for the use of mosquito nets.
Padilla flew to Turkey to attend a conference concerning the Liwanag ng Kapayapaan Foundation, a free preschool he built for Muslim children in Quezon City, which opened in 2007. On September 15, 2007 he donated 2.5 million Philippine pesos to the Muay Association of the Philippines.
Padilla was born to Casimero "Roy" Padilla, Sr. and Lolita Eva Cariño. He has seven siblings — three brothers and four sisters.
While serving a two-year prison sentence for illegal possession of narcotics, Padilla converted to Islam and married Liezl Sicangco in a Muslim ceremony at the New Bilibid Prison social hall. He was pardoned and released in 1998 by President Fidel Ramos. In November 2016, Padilla was granted an absolute pardon from President Rodrigo Duterte to endow him full civil and political rights.
He has four children with Liezl: a son named Ali and three daughters: Queenie, Kylie, who are actresses, and Zhen-Zhen. He also has a son named Mico with actress Jobelle Salvador and a daughter named Camille Orosa, a model and aspiring actress, with former model Leah Orosa.
His house in Greenview Executive Village, Novaliches, Quezon City was allegedly the subject of a break-in back in May 2008. his cellular phone and loaded .357 Luger handgun were reported as stolen.
In 2009, Padilla announced that he had divorced Sicangco and that she has since migrated and remarried in Australia.
On August 19, 2010, Padilla and Mariel Rodriguez were married at the Taj Mahal in India. Padilla and Rodriguez had met during his stint as a host of Wowowee. Rodriguez gave birth to their daughter, Maria Isabella, on November 14, 2016 in Delaware.
In July 2017, Padilla became a grandfather when his eldest daughter Queenie gave birth to her daughter.