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Clooney was born on May 6, 1961, in Lexington, Kentucky. His mother, Nina Bruce (née Warren), was a beauty queen and city councilwoman. His father, Nick Clooney, is a former anchorman and television host, including five years on the AMC network. Clooney is of Irish, German, and English ancestry. His maternal great-great-great-great-grandmother, Mary Ann Sparrow, was the half-sister of Nancy Lincoln, mother of President Abraham Lincoln. Clooney has an older sister named Adelia (known as Ada). Cabaret singer and actress Rosemary Clooney was an aunt. Through Rosemary, his cousins include actors Miguel Ferrer, Rafael Ferrer, and Gabriel Ferrer, who is married to singer Debby Boone.

Clooney was raised a strict Roman Catholic but said in 2006 that he did not know if he believed "in Heaven, or even God." He has said, "Yes, we were Catholic, big-time, whole family, whole group." He began his education at the Blessed Sacrament School in Fort Mitchell, Kentucky. He attended St. Michael's School in Columbus, Ohio; then Western Row Elementary School (a public school) in Mason, Ohio, from 1968 to 1974; and St. Susanna School in Mason, where he served as an altar boy. The Clooneys moved back to Kentucky when George was midway through the seventh grade. In middle school, Clooney developed Bell's palsy, a medical condition that partially paralyzes the face. The malady went away within a year. In an interview with Larry King, he stated that "yes, it goes away. It takes about nine months to go away. It was the first year of high school, which was a bad time for having half your face paralyzed." He also described one positive outcome of the condition: "It's probably a great thing that it happened to me because it forced me to engage in a series of making fun of myself. And I think that's an important part of being famous. The practical jokes have to be aimed at you."

After his parents moved to Augusta, Kentucky, Clooney attended Augusta High School. He has stated that he earned all As and a B in school, and played baseball and basketball. He tried out to play professional baseball with the Cincinnati Reds in 1977, but he did not pass the first round of player cuts and was not offered a contract. He attended Northern Kentucky University from 1979 to 1981, majoring in broadcast journalism, and very briefly attended the University of Cincinnati, but did not graduate from either. He earned money selling women's shoes, insurance door-to-door, stocking shelves, working in construction, and cutting tobacco.

Early work, 1978–1993

Clooney's first role was as an extra in the television mini-series Centennial in 1978, which was based on the novel of the same name by James A. Michener and was partly filmed in Clooney's hometown of Augusta, Kentucky. Clooney's first major role came in 1984 in the short-lived sitcom E/R (not to be confused with ER, the better-known hospital drama, on which Clooney also co-starred a decade later). He played a handyman on the series The Facts of Life and appeared as Bobby Hopkins, a detective, on an episode of The Golden Girls. His first prominent role was a semi-regular supporting role in the sitcom Roseanne, playing Roseanne Barr's supervisor Booker Brooks, followed by the role of a construction worker on Baby Talk, a co-starring role on the CBS drama Bodies of Evidence as Detective Ryan Walker, and then a year-long turn as Det. James Falconer on Sisters. In 1988, Clooney played a role in the comedy-horror film Return of the Killer Tomatoes. In 1990, he starred in the short-lived ABC police drama Sunset Beat. During this period, Clooney was a student at the Beverly Hills Playhouse acting school for five years.

Breakthrough, 1994–1999

Clooney rose to fame when he played Dr. Doug Ross, alongside Anthony Edwards, Julianna Margulies, and Noah Wyle, on the hit NBC medical drama ER from 1994 to 1999. After leaving the series in 1999, he made a cameo appearance in the 6th season and returned for a guest spot in the show's final season. For his work on the series, Clooney received two Primetime Emmy Award nominations for Outstanding Lead Actor in a Drama Series in 1995 and 1996. He also earned three Golden Globe Award nominations for Best Actor – Television Series Drama in 1995, 1996, and 1997 (losing to co-star Anthony Edwards).

Clooney began appearing in films while working on ER. His first major Hollywood role was in the horror comedy-crime thriller From Dusk till Dawn, directed by Robert Rodriguez and co-starring Harvey Keitel. He followed its success with the romantic comedy One Fine Day with Michelle Pfeiffer, and the action-thriller The Peacemaker with Nicole Kidman. Clooney was then cast as Batman in Joel Schumacher's Batman & Robin, which was a modest box office performer, but a critical failure (with Clooney himself calling the film "a waste of money"). In 1998, he co-starred in the crime-comedy Out of Sight opposite Jennifer Lopez, marking the first of his many collaborations with director Steven Soderbergh. He also starred in Three Kings during the last weeks of his contract with ER.

After ER, 2000–2010

After leaving ER, Clooney starred in the commercially successful films The Perfect Storm (2000), a disaster drama; and O Brother, Where Art Thou? (2000), a Coen brothers adventure comedy. In 2001, he teamed up with Soderbergh again for the heist comedy Ocean's Eleven, a remake of the 1960s Rat Pack film of the same name, with Clooney playing Danny Ocean, originally portrayed by Frank Sinatra. It is Clooney's most successful film with him in the lead role, earning $451 million worldwide (he appeared, but did not star, in Gravity, which has a $723 million worldwide box office). The film inspired two sequels starring Clooney, Ocean's Twelve in 2004 and Ocean's Thirteen in 2007.

In 2001, Clooney and Soderbergh co-founded Section Eight Productions, for which Grant Heslov was president of television. Clooney made his directorial debut in the 2002 film Confessions of a Dangerous Mind, based on the autobiography of TV producer Chuck Barris. Though the film did not do well at the box office, critics stated that Clooney's directing showed promise.

In 2005, Clooney starred in Syriana, which was based loosely on former Central Intelligence Agency agent Robert Baer's memoirs of his service in the Middle East. Clooney suffered an accident on the set of Syriana, which caused a brain injury with complications from a punctured dura. The same year he directed, produced, and starred in Good Night, and Good Luck, a film about 1950s television journalist Edward R. Murrow's famous war of words with Senator Joseph McCarthy. At the 2006 Academy Awards, Clooney was nominated for Best Director and Best Original Screenplay for Good Night, and Good Luck, as well as Best Supporting Actor for Syriana. He won the Oscar for his role in Syriana.

Clooney next appeared in The Good German (2006), a film noir directed by Soderbergh that is set in post-World War II Germany. In August 2006, Clooney and Heslov started the production company Smokehouse Pictures. In October 2006, Clooney received the American Cinematheque Award, which honors someone in the entertainment industry who has made "a significant contribution to the art of motion pictures". On January 22, 2008, Clooney was nominated for an Academy Award (and many other awards) for Best Actor for Michael Clayton (2007). Later that year, he directed his third film, Leatherheads, in which he also starred. On April 4, 2008, Variety reported that Clooney had quietly resigned from the Writers Guild of America over a dispute concerning Leatherheads. Clooney, who is the director, producer, and star of the film, claimed that he had contributed in writing "all but two scenes" of it, and requested a writing credit alongside Duncan Brantley and Rick Reilly, who had worked on the screenplay for 17 years. Clooney lost an arbitration vote 2–1, and withdrew from the union over the decision. He became a "financial core status" non-member, meaning he no longer has voting rights, and cannot run for office or attend membership meetings, according to the WGA's constitution.

He next co-starred with Ewan McGregor and Kevin Spacey in the war parody comedy film The Men Who Stare at Goats, which was directed by Heslov and released in November 2009. Also in November 2009, he voiced Mr. Fox in Wes Anderson's animated feature Fantastic Mr. Fox. The same year, Clooney starred in the comedy-drama Up in the Air, which was initially given limited release, and then wide-released on December 25, 2009. For his performanc