Penn appeared in a 1974 episode of the Little House on the Prairie television series as an extra when his father, Leo, directed some of the episodes. Penn launched his film career with the action-drama Taps (1981), where he played a military high school cadet. A year later, he appeared in the hit comedy Fast Times at Ridgemont High (1982), in the role of surfer-stoner Jeff Spicoli; his character helped popularize the word “dude” in popular culture. Next, Penn appeared as Mick O’Brien, a troubled youth, in the drama Bad Boys (1983). The role earned Penn favorable reviews and jump-started his career as a serious actor.

He met singer-songwriter Madonna in February 1985, and they married that August on her 27th birthday; Penn turned 25 the next day. The two starred in the panned and much-derided Shanghai Surprise (1986), directed by Jim Goddard, and Madonna dedicated her third studio album True Blue (1986) to Penn, referring to him in the liner notes as “the coolest guy in the universe”. The marriage was marred by violent outbursts against the press, including one incident when Penn was arrested for assaulting a photographer on a film set; Penn was sentenced to 60 days in jail in mid-1987, of which he served 33 days. Madonna filed for divorce in December 1987 but later withdrew the papers, only to file them again in January 1989. Madonna reportedly filed an assault complaint that she was beaten in her Malibu, California home by her estranged husband, but in January 1989, the Associated Press reported that she had “dropped assault charges.” Penn was alleged to have struck Madonna on multiple occasions, but in 2015 Madonna stated the allegations were “completely outrageous, malicious, reckless, and false”.

At the end of his first marriage, Penn moved in with actress Robin Wright, and their first child, a daughter named Dylan Frances, was born April 13, 1991. Their second child, son Hopper Jack, was born August 6, 1993. Penn and Wright separated in 1995, during which time he developed a relationship with Jewel, after he spotted her performing on Late Night with Conan O’Brien. He invited her to compose a song for his film The Crossing Guard (1995) and followed her on tour.

Penn and Wright reconciled, married on April 27, 1996, and lived in Ross, California. The couple filed for divorce in December 2007 but reconciled several months later, requesting a court dismissal of their divorce case. In April 2009, Penn filed for legal separation, only to withdraw the case once again when the couple reconciled in May. On August 12, 2009, Wright filed for divorce again. The couple’s divorce was finalized on July 22, 2010; the couple reached a private agreement on child and spousal support, division of assets, and custody of Hopper, who was almost 17 at the time.

Penn played Andrew Daulton Lee in the film The Falcon and the Snowman (1985), which closely followed an actual criminal case. Lee was a former drug dealer by trade, convicted of espionage for the Soviet Union and originally sentenced to life in prison, but was paroled in 1998. Penn later hired Lee as his personal assistant, partly because he wanted to reward Lee for allowing him to play Lee in the film; Penn was also a firm believer in rehabilitation and thought Lee should be successfully reintegrated into society, since he was a free man again.

Penn has been outspoken in supporting numerous political and social causes. On December 13–16, 2002, he visited Iraq to protest the Bush Administration’s apparent plans for a military strike on Iraq. On June 10, 2005, Penn made a visit to Iran. Acting as a journalist on an assignment for the San Francisco Chronicle, he attended a Friday prayer at Tehran University. On January 7, 2006, Penn was a special guest at the Progressive Democrats of America, where he was joined by author and media critic Norman Solomon and activist Cindy Sheehan. The “Out of Iraq Forum”, which took place in Sacramento, California, was organized to promote the anti-war movement calling for an end to the War in Iraq.

On October 18, 2002, Penn placed a $56,000 advertisement in the Washington Post asking then President George W. Bush to end a cycle of violence. It was written as an open letter and referred to the planned attack on Iraq and the War on Terror.

In the letter, Penn also criticized the Bush administration for its “deconstruction of civil liberties” and its “simplistic and inflammatory view of good and evil.” Penn visited Iraq briefly in December 2002. “Sean is one of the few,” remarked his ex-wife Madonna. “Good for him. Most celebrities are keeping their heads down. Nobody wants to be unpopular. But then Americans, by and large, are pretty ignorant of what’s going on in the world.” The Post advertisement was cited as a primary reason for the development of his relationship with Venezuelan president Hugo Chávez. In one of his televised speeches, Chávez used and read aloud an open letter Penn wrote to Bush. The letter condemned the Iraq War, called for Bush to be impeached, and also called Bush, Vice President Dick Cheney, and Secretary of State Condoleezza Rice “villainously and criminally obscene people.”

The Academy Awards first recognized his work in nominating him for playing a racist murderer on death row in the drama film Dead Man Walking (1995). He was nominated again for his comedic performance as an egotistical jazz guitarist in the film Sweet and Lowdown (1999). He received his third nomination after portraying a mentally handicapped father in I am Sam (2001). Penn finally won for his role in the Boston crime-drama Mystic River (2003). In 2004, Penn played Samuel Bicke, a character based on Samuel Byck, who in 1974 attempted and failed to assassinate President Richard Nixon, in The Assassination of Richard Nixon (2004). The same year, he was invited to join the Academy of Motion Picture Arts and Sciences. Next, Penn portrayed governor Willie Stark (based on Huey Long) in an adaptation of Robert Penn Warren’s classic 1946 American novel All the King’s Men (2006). The film was a critical and commercial failure, named by a 2010 Forbes article as the biggest flop in the last five years.

In September 2005, Penn traveled to New Orleans, Louisiana, to aid Hurricane Katrina victims. He was physically involved in rescuing people, although there was criticism that his involvement was a PR stunt as he hired a photographer to come along with his entourage. Penn denied such accusations in an article he wrote for The Huffington Post. Director Spike Lee interviewed Penn for Lee’s documentary about Hurricane Katrina, When the Levees Broke: A Requiem in Four Acts (2006).

Penn was born in Santa Monica, California, to actor and director Leo Penn, and actress Eileen Ryan (née Annucci). His older brother is musician Michael Penn. His younger brother, actor Chris Penn, died in 2006. His paternal grandparents were Jewish emigrants from the Russian Empire, while his mother is a Catholic of Irish and Italian descent. Penn was raised in a secular home in Malibu, California, and attended Malibu Park Junior High School and Santa Monica High School, as Malibu had no high school at that time. He began making short films with some of his childhood friends, including actors Emilio Estevez and Charlie Sheen, who lived near his home.

On December 18, 2006, Penn received the Christopher Reeve First Amendment Award from the Creative Coalition for his commitment to free speech. In August 2008, Penn made an appearance at one of Ralph Nader’s “Open the Debates” Super Rallies. He protested the political exclusion of Nader and other third parties. In October 2008, Penn traveled to Cuba, where he met with and interviewed President Raúl Castro. In February 2012, he stood beside Hugo Chávez while Venezuela supported the Syrian government during the 2011–2012 Syrian uprising.

On April 19, 2007, Penn appeared on The Colbert Report and had a “Meta-Free-Phor-All” versus Stephen Colbert that was judged by Robert Pinsky. This stemmed from some of Penn’s criticisms of Bush. His exact quote was “We cower as you point your fingers telling us to support our troops. You and the smarmy pundits in your pocket– those who bathe in the moisture of your soiled and blood-soaked underwear– can take that noise and shove it.” He won the contest with 10,000,000 points to Colbert’s 1. On December 7, 2007, Penn said he supported Ohio Congressman Dennis J. Kucinich for U.S. President in 2008, and criticized Bush’s handling of the Iraq war. Penn questioned whether Bush’s twin daughters supported the war in Iraq.

In November 2008, Penn earned positive reviews for his portrayal of real-life gay-rights icon and politician Harvey Milk in the biopic Milk (2008), and was nominated for best actor for the 2008 Independent Spirit Awards. The film also earned Penn his fifth nomination and second win for the Academy Award for Best Actor. Penn starred as Joseph C. Wilson in Fair Game (2010), a film adaptation of Valerie Plame’s 2007 memoir. He co-starred in the drama The Tree of Life (2011), which won the Palme d’Or at the 2011 Cannes Film Festival. In 2015, Penn starred in The Gunman, a French-American action thriller based on the novel The Prone Gunman, by Jean-Patrick Manchette. Jasmine Trinca, Idris Elba, Ray Winstone, Mark Rylance, and fellow Oscar-winner Javier Bardem appear in supporting roles. Penn plays Jim Terrier, a sniper on a mercenary assassination team who kills the minister of mines of the Congo.

On February 22, 2009, Penn received the Academy Award for Best Actor for the film Milk. In his acceptance speech, he said: “I think that it is a good time for those who voted for the ban against gay marriage to sit and reflect and anticipate their great shame and the shame in their grandchildren’s eyes if they continue that way of support. We’ve got to have equal rights for everyone!”

After the 2010 Haiti earthquake, Penn founded the J/P Haitian Relief Organization, which operated a 55,000 person tent camp. Before starting the organization, Penn had never visited Haiti and did not speak French or Creole. When asked for his comment on critics who questioned his experience, he said he hopes they “die screaming of rectal cancer”. Due to his visibility as an on-the-ground advocate for rescue and aid efforts in the aftermath, Penn was designated by president Michel Martelly as Ambassador-at-Large for Haiti, the first time that a non-Haitian citizen has been designated as such in the country’s history. Penn received the designation on January 31, 2012. In 2012, at the 12th World Summit of Nobel Peace Laureates, Penn received the Peace Summit Award.

In March 2010, Penn called for the arrest of those referring to Venezuelan President Hugo Chávez as a dictator. The two were friends, and when Chávez died in 2013, Penn said: “Venezuela and its revolution will endure under the proven leadership of Vice President Nicolás Maduro. Today the United States lost a friend it never knew it had. And poor people around the world lost a champion. I lost a friend I was blessed to have.”

Penn gained significant attention in the Pakistan media when he visited Karachi and Badin in 2012. On March 23, 2012, he visited flood-stricken villages of Karim Bux Jamali, Dargah Shah Gurio and Peero Lashari in Badin District. He was accompanied by U.S. Consul General William J. Martin and distributed blankets, quilts, kitchen items and other goods amongst flood survivors.

On March 24, 2012, Penn also visited Bilquis Edhi Female Child Home and met Pakistan’s iconic humanitarian worker Abdul Sattar Edhi and his wife, Bilquis Edhi. He also laid floral wreaths and paid respect at the shrine of Abdullah Shah Ghazi.

In February 2012, Penn met with the President of Argentina, Cristina Fernández de Kirchner, in Buenos Aires where he made a statement on the long-running dispute between Argentina and the United Kingdom over the Falkland Islands, saying: “I know I came in a very sensitive moment in terms of diplomacy between Argentina and the UK over the Falkland Islands. And I hope that diplomats can establish true dialogue in order to solve the conflict as the world today cannot tolerate ridiculous demonstrations of colonialism. The way of dialogue is the only way to achieve a better solution for both nations.”

From 2013 to 2015, Penn was in a relationship with South African actress Charlize Theron.

Penn is believed to have played a role in getting American entrepreneur Jacob Ostreicher released from a Bolivian prison in 2013, and was credited by Ostreicher for having personally nursed him back to health upon his release.

He began a relationship with Australian actress Leila George in 2016. They married on July 30, 2020.

In an interview published September 16, 2015, director and showrunner Lee Daniels responded to criticism about Terrence Howard’s continued career in light of his domestic violence issues by referencing Penn’s rumored history of domestic violence, saying: “[Terrence] ain’t done nothing different than Marlon Brando or Sean Penn, and all of a sudden he’s some f—in’ demon.” In response, Penn launched a $10 million defamation suit against Daniels, alleging that he had never been arrested for or charged with domestic violence. Penn dropped the lawsuit in May 2016 after Daniels retracted his statement and apologized.

A day after Mexican officials announced the capture of Joaquín “El Chapo” Guzmán in a bloody raid, Rolling Stone revealed on January 9, 2016 that Sean Penn, along with actress Kate del Castillo, had conducted a secret interview with El Chapo prior to his arrest. Del Castillo was contacted by Guzmán’s lawyer (who was under CISEN surveillance) to talk about producing a biographical film about Guzmán and communication increased following Guzmán’s escape from prison in July 2015. The deal for the interview was brokered by del Castillo. According to published text messages with del Castillo, Guzmán did not know who Sean Penn was. CISEN released photographs of del Castillo at the meetings with Guzmán’s lawyers and of the arrival of the actress and Penn to Mexico. The interview was criticized by some, including the White House, which called the interview “maddening”. Mexican authorities said they were seeking to question Penn over the interview, which had not been approved by either the American or Mexican government. Penn and del Castillo’s meeting with Guzmán is under investigation by the Attorney General of Mexico.

In March 2018, Atria Books published Penn’s novel Bob Honey Who Just Do Stuff. After the book’s release, Penn went on a highly publicized press tour. He claimed that he no longer had “a generic interest in making films”, and being a writer will “dominate my creative energies for the foreseeable future.”

In October 2020, Penn tweeted in support of Armenia in regards to the Nagorno-Karabakh war between Armenia and Azerbaijan. He also criticized Turkey’s involvement in the conflict and close Turkey–United States ties. He stated: “Armenians are being slaughtered by Trump pal Erdogan with weapons WE provided. THIS is NOT America! Biden for America’s new birth!”.