Howard Hughes in Hollywood

Hughes was at first dismissed by Hollywood insiders as a rich man's son. However, his first two films, 1927's Everybody's Acting and 1928's Two Arabian Knights, were financial successes, the latter winning an Academy Award for Best Director of a Comedy Picture. 1928's The Racket and 1931's The Front Page were nominated for Academy Awards. Hughes spent a then-unheard-of $3.8 million of his own money to make Hell's Angels, an epic flying film that ultimately became a smash hit after overcoming many obstacles, released in 1930. He produced another hit, Scarface, in 1932. One of his best-known films may be The Outlaw which made a star of Jane Russell, for whom Hughes designed a special bra (although Russell decided against wearing the bra because of a mediocre fit). Scarface and The Outlaw both received considerable attention from industry censors; Scarface for its violence, The Outlaw due to Russell's revealing costumes.

He signed an unknown actor, David Bacon, in 1942 to play Billy the Kid, and then later replaced him with Jack Buetel. According to Albert "Cubby" Broccoli and Lucien Ballard, both of whom worked on The Outlaw, Hughes and Buetel had a sexual relationship, which also influenced Bacon's replacement in the movie. Bacon's murder the following year sparked an investigation which brought to light allegations of the affair between them and which may have indirectly led to Bacon's death. Bacon's widow, Greta Keller, claimed later that he wanted to get out of his contract with Hughes and had been prepared to reveal details about their alleged homosexual relationship in order to secure a release from the studio. However, according to the book written by Brown and Boeske, hundreds of depositions from Hughes' associates have never revealed any evidence that he was gay.

Hughes kept his wife isolated at home for weeks at a time and, in 1929, she returned to Houston and filed for divorce. Hughes was a notorious ladies' man who spent time with many famous women, including Billie Dove, Katharine Hepburn, Bette Davis, Ava Gardner, Olivia de Havilland and Gene Tierney. He also proposed to Joan Fontaine several times, according to her autobiography No Bed of Roses. Bessie Love was a mistress during his first marriage. Jean Harlow accompanied him to the premiere of Hell's Angels, but Hughes' longtime, right-hand man, Noah Dietrich, wrote many years later that the relationship was strictly professional—Hughes personally disliked Harlow. In his 1971 book, Howard: The Amazing Mr. Hughes, Dietrich also noted that Hughes genuinely liked and respected Jane Russell but never sought romantic involvement with her. According to Russell's autobiography, however, Hughes once tried to bed her after a party. Russell (who was married at the time) refused him and Hughes promised it would never happen again. The two maintained a professional and private friendship for many years. Hughes remained good friends with Tierney – when Tierney's daughter Daria who was born deaf and blind with severe mental retardation due to Tierney being exposed to the German Measles during her pregnancy, he saw to it that Daria received the best medical care and paid all expenses. Tierney never forgot his acts of kindness.

On 11 July 1936, a car driven by Hughes struck and killed a pedestrian named Gabriel Meyer at the corner of Third Street and Lorraine in Los Angeles. Although Hughes was certified as sober at the hospital to which he was taken after the accident, a doctor there made a note that Hughes had been drinking. He was taken to jail and booked on "suspicion of negligent homicide." A witness to the accident told police that Hughes was driving erratically and too fast, and that Meyer had been standing in the safety zone of a streetcar stop. By the time of the coroner's inquiry, however, the witness had changed his story and claimed that Meyer had moved directly in front of Hughes' car. Hughes made the same claim to reporters outside the inquiry, saying, "I was driving slowly and a man stepped out of the darkness in front of me." The District Attorney recommended that Hughes be cleared of responsibility for Meyer's death.

In 1956, he released The Conqueror, considered a tremendous flop and particularly infamous for what was considered a miscasting of John Wayne as Genghis Khan.

On 12 January 1957, Hughes married actress Jean Peters, whom he had known in Hollywood for several years. His second marriage was troubled, however, with much of the contact between husband and wife conducted by phone.