Roscoe Conkling Arbuckle was born on March 24, 1887 in Smith Center, Kansas, one of nine children of Mary E. "Mollie" Gordon (d. February 19, 1898) and william Goodrich Arbuckle. He weighed in excess of 13 lb (5.9 kg) at birth and, as both parents had slim builds, his father believed the child was not his. Consequently, he named the baby after a Politician (and notorious philanderer) whom he despised, Republican senator Roscoe Conkling of New York. The birth was traumatic for Mollie and resulted in chronic health problems that contributed to her death 12 years later.

When Arbuckle was nearly two his family moved to Santa Ana, California. Roscoe had a "wonderful" singing voice and was extremely agile. At the age of eight, with his mother's encouragement, he first performed on stage with Frank Bacon's company during their stopover in Santa Ana. Arbuckle enjoyed performing and continued on until his mother's death in 1899 when he was 12. His father, who had always treated him harshly, now refused to support him and Arbuckle got work doing odd jobs in a hotel. Arbuckle was in the habit of singing while he worked and was overheard by a customer who was a professional singer. The customer invited him to perform in an amateur talent show. The show consisted of the audience judging acts by clapping or jeering with bad acts pulled off the stage by a shepherd's crook. Arbuckle sang, danced, and did some clowning around, but did not impress the audience. He saw the crook emerge from the wings and to avoid it somersaulted into the orchestra pit in obvious panic. The audience went wild, and he not only won the competition but began a career in vaudeville.

In 1904, Sid Grauman invited Arbuckle to sing in his new Unique Theater in San Francisco, beginning a long friendship between the two. He then joined the Pantages Theatre Group touring the West Coast of the United States and in 1906 played the Orpheum Theater in Portland, Oregon in a vaudeville troupe organized by Leon Errol. Arbuckle became the main act and the group took their show on tour.

On August 6, 1908, Arbuckle married Minta Durfee (1889–1975), the daughter of Charles Warren Durfee and Flora Adkins. Durfee starred in many early comedy films, often with Arbuckle. They made a strange couple, as Minta was short and petite while Arbuckle tipped the scales at 300 lbs. Arbuckle then joined the Morosco Burbank Stock vaudeville company and went on a tour of China and Japan returning in early 1909.

Arbuckle began his film career with the Selig Polyscope Company in July 1909 when he appeared in Ben's Kid. Arbuckle appeared sporadically in Selig one-reelers until 1913, moved briefly to Universal Pictures and became a star in producer-director Mack Sennett's Keystone Cops comedies (However, according to the Motion Picture Studio Directory for 1919 and 1921, Arbuckle began his screen career with Keystone in 1913 as an extra for $3 a day (equivalent to approximately $74 in 2017 dollars), working his way up through the acting ranks to become a lead player and Director.) Although his large size was undoubtedly part of his comedic appeal Arbuckle was self-conscious about his weight and refused to use it to get "cheap" laughs. For Example, he would not allow himself to be stuck in a doorway or chair.

Despite his physical size, Arbuckle was remarkably agile and acrobatic. Director Mack Sennett, when recounting his first meeting with Arbuckle, noted that he "skipped up the stairs as lightly as Fred Astaire"; and, "without warning went into a feather light step, clapped his hands and did a backward somersault as graceful as a girl tumbler". His comedies are noted as rollicking and fast-paced, have many chase scenes, and feature sight gags. Arbuckle was fond of the "pie in the face", a comedy cliché that has come to symbolize silent-film-era comedy itself. The earliest known pie thrown in film was in the June 1913 Keystone one-reeler A Noise from the Deep, starring Arbuckle and frequent screen partner Mabel Normand.

Arbuckle was regarded by those who knew him closely as a good-natured man who was shy with women; he has been described as "the most chaste man in pictures". However, studio executives, fearing negative publicity by association, ordered Arbuckle's industry friends and fellow actors (whose careers they controlled) not to publicly speak up for him. Charlie Chaplin, who was in Britain at the time, told reporters that he could not (and would not) believe Roscoe Arbuckle had anything to do with Virginia Rappe's death; having known Arbuckle since they both worked at Keystone in 1914, Chaplin "knew Roscoe to be a genial, easy-going type who would not harm a fly." Buster Keaton reportedly did make one public statement in support of Arbuckle's innocence which earned him a mild reprimand from the studio where he worked. Film actor william S. Hart, who had never met or worked with Arbuckle, made a number of damaging public statements in which he presumed that Arbuckle was guilty. Arbuckle later wrote a premise for a film parodying Hart as a thief, bully, and wife beater, which Keaton purchased from him. The following year in 1922, Keaton co-wrote, directed and starred in The Frozen North, the resulting film, and as a result, Hart refused to speak to Keaton for many years.

By 1916, Arbuckle was experiencing serious health problems. An infection that developed on his leg became a carbuncle so severe that doctors considered amputation. Although Arbuckle was able to keep his leg, he became addicted to the pain killer morphine.

Following his recovery, Arbuckle started his own film company, Comique, in partnership with Joseph Schenck. Although Comique produced some of the best short pictures of the silent era, in 1918 Arbuckle transferred his controlling interest in the company to Buster Keaton and accepted Paramount's $3 million offer to make up to 18 feature films over three years.

Many of Arbuckle's films, including the feature Life of the Party (1920), survive only as worn prints with foreign-language inter-titles. Little or no effort was made to preserve original negatives and prints during Hollywood's first two decades. By the early 21st century, some of Arbuckle's short subjects (particularly those co-starring Chaplin or Keaton) had been restored, released on DVD, and even screened theatrically. Arbuckle's early influence on American slapstick comedy is widely recognised.

During the whole trial, the prosecution presented medical descriptions of Rappe's bladder as evidence that she had an illness. In his testimony, Arbuckle denied he had any knowledge of Rappe's illness. During cross-examination, Assistant District Attorney Leo Friedman aggressively grilled Arbuckle over the fact that he refused to call a Doctor when he found Rappe sick, and argued that he refused to do so because he knew of Rappe's illness and saw a perfect opportunity to rape and kill her. Arbuckle calmly maintained that he never physically hurt or sexually assaulted Rappe in any way during the September 5 party, and he also claimed that he never made any inappropriate sexual advances against any woman in his life. After over two weeks of testimony with 60 prosecution and defense witnesses, including 18 doctors who testified about Rappe's illness, the defense rested. On December 4, 1921, the jury returned five days later deadlocked after nearly 44 hours of deliberation with a 10–2 not guilty verdict, and a mistrial was declared.

Arbuckle tried returning to filmmaking, but industry resistance to distributing his pictures continued to linger after his acquittal. He retreated into alcoholism. In the words of his first wife, "Roscoe only seemed to find solace and comfort in a bottle". Buster Keaton attempted to help Arbuckle by giving him work on his films. Arbuckle wrote the story for a Keaton short called Daydreams (1922). Arbuckle allegedly co-directed scenes in Keaton's Sherlock, Jr. (1924), but it is unclear how much of this footage remained in the film's final cut. In 1925, Carter Dehaven made the short Character Studies. Arbuckle appeared alongside Buster Keaton, Harold Lloyd, Rudolph Valentino, Douglas Fairbanks, and Jackie Coogan. The same year, in Photoplay's August issue, James R. Quirk wrote "I would like to see Roscoe Arbuckle make a comeback to the screen." He also said "The American nation prides itself upon its spirit of fair play. We like the whole world to look upon America as the place where every man gets a square deal. Are you sure Roscoe Arbuckle is getting one today? I'm not."

Between 1924 and 1932, Arbuckle directed a number of comedy shorts under the pseudonym for Educational Pictures, which featured lesser-known comics of the day. Louise Brooks, who played the ingenue in Windy Riley Goes Hollywood (1931), told Kevin Brownlow of her experiences in working with Arbuckle:

After the trials, Hollywood shunned Arbuckle, and he could no longer find work. A secondary effect, for archive history, was the determined destruction of copies of films starring Arbuckle. In November 1923, Minta Durfee filed for divorce, charging grounds of desertion. The divorce was granted the following January. They had been separated since 1921, though Durfee always claimed he was the nicest man in the world and they were still friends. After a brief reconciliation, Durfee again filed for divorce, this time while in Paris, in December 1924. Arbuckle married Doris Deane on May 16, 1925.

Among the more visible directorial projects under the Goodrich pseudonym was the Eddie Cantor feature Special Delivery (1927), which was released by Paramount and co-starred william Powell and Jobyna Ralston. His highest-profile project was arguably The Red Mill, also released in 1927, a Marion Davies vehicle.

In 1932, Arbuckle signed a contract with Warner Bros. to star under his own name in a series of six two-reel comedies, to be filmed at the Vitagraph studios in Brooklyn. These six short films constitute the only recordings of his voice. Silent-film Comedian Al St. John (Arbuckle's nephew) and actors Lionel Stander and Shemp Howard appeared with Arbuckle. The films were very successful in America, although when Warner Bros. attempted to release the first one (Hey, Pop!) in the United Kingdom, the British Board of Film Censors cited the 10-year-old scandal and refused to grant an exhibition certificate.

On June 28, 1933, Arbuckle had finished filming the last of the two-reelers (four of which had already been released). The next day he signed a contract with Warners to star in a feature-length film. That night he went out with friends to celebrate his first wedding anniversary and the new Warner contract when he reportedly said: "This is the best day of my life." He suffered a heart attack later that night and died in his sleep. He was 46. His widow Addie requested that his body be cremated as that was Arbuckle's wish.

Eventually, Arbuckle worked as a Director under the alias William Goodrich. According to author David Yallop in The Day the Laughter Stopped (a biography of Arbuckle with special attention to the scandal and its aftermath), Arbuckle's father's full name was william Goodrich Arbuckle. Another tale credited Keaton, an inveterate punster, with suggesting that Arbuckle become a Director under the alias "Will B. Good". The pun being too obvious, Arbuckle adopted the more formal pseudonym "William Goodrich". Keaton himself told this story during a recorded interview with Kevin Brownlow in the 1960s.

The James Ivory film The Wild Party (1975) has been repeatedly but incorrectly cited as a film dramatization of the Arbuckle–Rappe scandal. In fact it is loosely based on the 1926 poem by Joseph Moncure March. In this film, James Coco portrays a heavy-set silent-film Comedian named Jolly Grimm whose career is on the skids, but who is desperately planning a comeback. Raquel Welch portrays his mistress, who ultimately goads him into shooting her. This film was loosely based on the misconceptions surrounding the Arbuckle scandal, yet it bears almost no resemblance to the documented facts of the case.

In Ken Russell's 1977 biopic Valentino, Rudolph Nureyev as a pre-movie star Rudolph Valentino dances in a nightclub before a grossly overweight, obnoxious, and hedonistic Celebrity called "Mr. Fatty" (played by william Hootkins), a caricature of Arbuckle rooted in the public view of him created in popular press coverage of the Rappe rape trial. In the scene, Valentino picks up starlet (Jean Acker played by Carol Kane) off a table in which she is sitting in front of Fatty and dances with her, enraging the spoiled star, who becomes apoplectic. The caricature of Arbuckle as a boor continued to be promulgated in the seventies by film Writers such as Kenneth Anger in his seminal work Hollywood Babylon.

Fatty Arbuckle's was an American-themed restaurant chain in the UK prominent during the 1980s and named after Arbuckle.

Before his death in 1997, Comedian Chris Farley expressed interest in starring as Arbuckle in a biography film. According to the 2008 biography The Chris Farley Show: A Biography in Three Acts, Farley and Screenwriter David Mamet agreed to work together on what would have been Farley's first dramatic role. In 2007, Director Kevin Connor planned a film, The Life of the Party, based on Arbuckle's life. It was to star Chris Kattan and Preston Lacy. However the project was shelved. Like Farley, comedians John Belushi and John Candy also considered playing Arbuckle, but each of them died before a biopic was made. Farley's film was signed with Vince Vaughn as his co-star.

Arbuckle is the subject of a 2004 novel titled I, Fatty by author Jerry Stahl. The Day the Laughter Stopped by David Yallop and Frame-Up! The Untold Story of Roscoe "Fatty" Arbuckle by Andy Edmonds are other books on Arbuckle's life. The 1963 novel, Scandal in Eden by Garet Rogers, is a fictionalized version of the Arbuckle scandal.

In 2005, jazz trumpet player Dave Douglas released the album "Keystone", dedicated to the work of Roscoe Arbuckle. It contains a DVD which features the movie Fatty and Mabel Adrift (1916/ Keystone – Triangle), starring Roscoe Arbuckle, Mable Normand, Al St. John, and Luke the Dog.

In April and May 2006, the Museum of Modern Art in New York City mounted a 56-film, month-long retrospective of all of Arbuckle's known surviving work, running the entire series twice.

Stoneface, a 2012 play by Vanessa Claire Stewart about Buster Keaton, depicts Keaton's and Arbuckle's friendship and professional relationship.

Arbuckle is played by actor Brett Ashy in the motion picture Return to Babylon (2013).

Arbuckle disliked his screen nickname. "Fatty" had also been Arbuckle's nickname since school; "It was inevitable", he said. He weighed 185lb (13st 3lb, 84kg) when he was 12. Fans also called Roscoe "The Prince of Whales" and "The Balloonatic". However, the name Fatty identifies the character that Arbuckle portrayed on-screen (usually a naive hayseed)—not Arbuckle himself. When Arbuckle portrayed a female, the character was named "Miss Fatty", as in the film Miss Fatty's Seaside Lovers. Arbuckle discouraged anyone from addressing him as "Fatty" off-screen, and when they did so his usual response was, "I've got a name, you know."

Some experts later concluded that Rappe's bladder might also have ruptured as a result of an abortion she might have had a short time before the September 5 party. Rappe's organs had been destroyed and it was now impossible to test for pregnancy. Because alcohol was consumed at the party, Arbuckle was forced to plead guilty to one count of violating the Volstead Act, and had to pay a $500 fine. At the time of his acquittal, Arbuckle owed over $700,000 (equivalent to approximately $10,200,000 in 2017 dollars) in legal fees to his attorneys for the three Criminal trials, and he was forced to sell his house and all of his cars to pay some of the debt.