The Aviator has no opening credits other than the title. The film begins in 1914 with nine-year-old Hughes being bathed by his mother, who warns him of disease: "You are not safe."
The film next shows him in 1927, as a 22-year old preparing to direct Hell's Angels. Hiring Noah Dietrich (John C. Reilly) to run Hughes Tool Co, while he oversees the flight sequences for the film, Hughes becomes obsessed with shooting the film realistically, even re-shooting the dogfight himself. By 1929, with the film finally complete, when The Jazz Singer is released, Hughes re-shoots the film for sound, costing another year and $1.7 million. Nevertheless, Hell's Angels is a huge hit, and Hughes makes Scarface and The Outlaw. However, there is one goal he relentlessly pursues: aviation. During this time, he also pursues Katharine Hepburn (Cate Blanchett). The two go to nightclubs, play golf and fly together, and as they grow closer, move in together as well. During this time Hepburn becomes a major support and confidant to Hughes, and helps alleviate the symptoms of his obsessive-compulsive disorder. As Hughes' fame grows, he is seen with more starlets.
Hughes takes an interest in commercial-passenger travel, and purchases majority interest in Transcontinental & Western Air (TWA), the predecessor to Trans World Airlines. In 1935, he test flies the H-1 Racer but crashes in a beet field; "Fastest man on the planet," he boasts to Hepburn. Three years later, he flies around the world in four days, shattering the previous record by three days. Meanwhile, Juan Trippe (Alec Baldwin), owner of Pan American Airlines, and Senator Owen Brewster (Alan Alda) worry over the possibility that Hughes might beat them in the quest for commercial expansion. Brewster has just introduced the Commercial Airline Bill, which will give world expansion solely to Pan Am. Trippe advises Brewster to check to the "disquieting rumors about Mr. Hughes."
Hepburn and Hughes eventually break up when she announces that she has fallen in love with her movie costar (although he is briefly seen but never clearly stated, the viewers already know that the costar is her would be life-long partner Spencer Tracy).
He soon has a new interest: 15-year old Faith Domergue (Kelli Garner) and later, Ava Gardner (Kate Beckinsale). He also fights the Motion Picture Association of America over the steamy scenes in The Outlaw. He learns of Pan Am's efforts to run TWA off the map yet secures contracts with the Army Air Force on two projects, a spy plane and a troop transport. By 1946, Hughes has only finished the XF-11 reconnaissance aircraft and is building the H-4 Hercules ("Spruce Goose") flying boat.
With the strain of meeting deadlines and budgets, Hughes starts to show signs of alarming behavior, repeating phrases over and over and exhibiting a phobia over dust and germs. That July, he takes the XF-11 for a test flight. One of the propellers malfunctions, causing a crash in a Beverly Hills neighborhood. Rushed to the hospital, he slowly recuperates but learns the H-4 Hercules transport is no longer needed but orders production to continue. When he is discharged, the whole TWA fleet is built and ready to go, but he is in danger of being bankrupted by the airline and his flying boat.
Afraid of the media trying to find him, Hughes places microphones and taps Ava's phone lines to keep track of any suspicious activity. After being confronted by Gardner, he returns home to find the FBI searching his house for incriminating evidence that he embezzled government funds. The incident is both a powerful trauma for Hughes and gives his enemies knowledge about his condition. Hughes meets with Brewster, who offers to drop the charges if Hughes supports the CAB Bill and sells the TWA stock to Trippe. Hughes sinks into a deep depression afterwards, shutting himself in his screening room, growing ever more paranoid and detached from reality; terrified of germs, he urinates into dozens of empty milk bottles. Hepburn tries to visit him, but is unable to help. Trippe then pays Hughes a visit, but an enraged Hughes vows he will never sell TWA. Trippe warns Dietrich that the world will see what Hughes has become if he goes to the Hearings. After nearly three months, Hughes finally emerges and prepares to face the Senate, with encouragement from Ava Gardner, who helps him get cleaned up.
Hughes arrives at the hearings, and starts off with counter-claiming Brewster's charges: "Why not tell the truth, Senator? Why not tell the truth that this investigation was really born on the day that TWA first decided to fly to Europe?" Humiliated and enraged by this turn of events, Brewster formally states that Hughes charged the Defense Department $56 million for aircraft that never flew. Hughes defends himself and reveals that Trippe essentially bribed Brewster to hold the hearings.
The H-4 hercules "Spruce Goose" transport
Hughes successfully test flies the flying boat himself. After the flight, he talks to Dietrich and his mechanic Odie (Matt Ross) about a new jetliner for TWA (The Convair 880 Coronado) and makes a date with Gardner at a celebration party on the Long Beach shoreline. Hughes seems free of his inner demons until he sees three attendants in business suits and white gloves edging towards him, which triggers an obsessive-compulsive fit as he begins repeating "The way of the future." Dietrich and Odie take Hughes in a bathroom and hide him there, while Dietrich fetches a doctor and Odie stands outside guarding the door. Alone inside, Howard has a flashback to his boyhood, being washed by his mother and resolving he will fly the fastest aircraft ever built, make the biggest movies ever and become the richest man in the world. As the film ends he mutters "the way of the future... the way of the future" into a darkened mirror.