In 1952, Ed Wood is struggling to enter the film industry. Upon hearing of an announcement in Variety magazine that producer George Weiss is trying to purchase Christine Jorgensen’s life story, Wood wants to meet Weiss. Weiss explains that Variety’s announcement was a news leak, and it is impossible to purchase Jorgensen’s rights. The producer decides to fictionalize the film, titled I Changed My Sex!. Wood tries to convince Weiss that he is perfect to direct the film, owing to the fact that he himself is a closeted transvestite and knows what it is like to live with a secret and worry what people might think, but is unsuccessful since Weiss wants a director with experience. Wood meets his longtime idol Bela Lugosi and the two become friends. Wood persuades Weiss to let him direct the film by convincing him that having a star in the film would sell tickets, and they could sign Lugosi for a low price.
Wood and Weiss argue over the film’s title and subject matter: Weiss has the poster printed, which Wood changes to Glen or Glenda and writes the film about a transvestite rather than a sex change. Weiss allows Wood to shoot whatever he wants as long as the film meets the required length. Wood takes to film production with an unusual approach; shooting only one take per scene, giving actors very little direction and using stock footage to fill in gaps. The movie is released to critical and commercial failure. Because of this, Wood is unsuccessful in getting a job at Weiss’ Screen Classics or making a partnership with Warner Bros. executive Feldman, but his girlfriend, Dolores Fuller, tells him that he should try financing his next film independently. Wood is unsuccessful in finding money for Bride of the Atom, but is introduced to a psychic called The Amazing Criswell who gives him advice on how to sell himself better.
Wood meets Loretta King, whom he thinks has enough money to fund Bride of the Atom and ends up casting her as the lead instead of Fuller as planned. Filming begins, but is halted when it is revealed that King is actually poor, and Wood has no money to continue production. Wood convinces meat packing industry tycoon Don McCoy to take over funding the film, who agrees as long as the film stars his son Tony as the leading man and the film ends with an explosion. The filming finishes with the title being changed to Bride of the Monster, but Fuller breaks up with Wood after the wrap party because of his circle of misfit friends, his work, and transvestism. Lugosi attempts to conduct a double suicide with Ed after the government cuts off his unemployment benefit, but is talked out of it. Lugosi checks himself into rehab, and Wood meets Kathy O’Hara, who is visiting her father there. He takes her on a date and reveals to her his transvestism, which she accepts.
Wood shoots a film with Lugosi outside his home. When Wood and company attend the premiere for Bride of the Monster, an angry mob chases them out of the theater. Lugosi passes away, leaving Wood without a star. Wood convinces his landlord, a church leader named Reynolds, that funding Wood’s script for Grave Robbers from Outer Space would result in a box-office success, and generate enough money for Reynolds’ dream project. Dr. Tom Mason, O’Hara’s chiropractor, is chosen to be Lugosi’s stand-in for resembling Lugosi. Wood and the Baptists have conflicts over the title and content of the script, which they want to have changed to Plan 9 from Outer Space, along with Ed’s B movie directing style, his casting decisions and his transvestism. Wood leaves the set to go to the nearest bar, where he encounters his idol, Orson Welles (a fictional encounter). Filming for Plan 9 finishes with Ed taking action against his producers’ wishes. After attending the premiere of Plan 9, Wood and O’Hara go to Las Vegas to get married.