It's 1927 and billionaire Howard Hughes (LEONARDO DICAPRIO) is bucking the system by making "Hell's Angels," the most expensive movie ever produced outside of the Hollywood system. After years of work and millions of dollars spent, he finally gets the movie finished with the aid of his assistant, Noah Dietrich (JOHN C. REILLY), press agent Johnny Meyer (ADAM SCOTT) and even meteorology Professor Fitz (IAN HOLM), who was brought in to find him the right clouds for the background of his shots. Soon, Hughes is hobnobbing with Hollywood celebrities such as Jean Harlow (GWEN STEFANI), Errol Flynn (JUDE LAW) and Katharine Hepburn (CATE BLANCHETT).
It's with the latter that he develops an affinity and the two quickly become lovers. Even so, his progressively worsening fear of germs and avid interest in aeronautical pursuits -- such as buying a controlling interest in TWA and designing, building and flying experimental aircraft that he uses to break various world records -- eventually drives her into the arms of another man.
Various women -- including actress Ava Gardner (KATE BECKINSALE) and the underage Faith Domergue (KELLI GARNER) -- take her place, but Howard continues on his quest to do things bigger and better than anyone before, including building war-related planes for the U.S. Government. Eventually, however, he runs into opposition from Juan Trippe (ALEC BALDWIN) of Pan Am, who wants the budding transcontinental flight market all to himself. With the aid of U.S Senate committee chairman Ralph Owen Brewster (ALAN ALDA), he desires to put Hughes out of business.
Struggling with his neurosis and various unexpected personal and professional setbacks, Hughes sets out to save his reputation and prove that he's still got what it takes to accomplish his goals and make a large and longstanding impression.