On Halloween 1950, an 11-year-old Harvey Pekar decides against dressing up as a typical superhero for trick-or-treating. Fast forward to the present, and we find Harvey navigating the streets of Cleveland, appearing in a documentary-style narrative. In 1975, Harvey pays a visit to a throat doctor, showcasing his hypochondriac tendencies. His lifestyle becomes a point of contention, leading to a mockery from his wife, who ultimately chooses to leave him. At the VA hospital where he works as a file clerk, a colleague named Mr. Boats offers him advice inspired by an Elinor Wylie poem, hinting at the complexities of Harvey's emotional state.
In a documentary interlude, the real Harvey shares insights about his passion for collecting and selling used records. Reflecting back to 1962, Harvey meets the reserved illustrator Robert Crumb at a yard sale, and they forge a connection over jazz music and comic books. Jumping back to 1975, Crumb, now more famous, pays a visit to Cleveland. Alone and frustrated, Harvey confronts the somber reality of the “deceased” files at work, prompting him to channel his experiences into writing. Inspired by a supermarket incident, he spends an entire night crafting his comic stories. During a diner meet-up with Crumb, he presents his scripts, leading Crumb to offer his artistic talents for illustration.
As a result, Harvey sees the launch of American Splendor, publishing eight acclaimed issues, yet his financial situation remains stagnant, and he continues his job at the VA hospital. He rekindles a relationship with Alice Quinn, a former college mate, and although they discuss important literary works such as Theodore Dreiser's Jennie Gerhardt, Harvey leaves their meeting feeling increasingly isolated.
In Delaware, Joyce becomes frustrated with her comic book store partner who sells her copy of American Splendor No. 8. When she reaches out to Harvey, they both discover a deep connection and soon, Joyce travels to Cleveland for their first meeting. After a dinner that takes a turn when Joyce falls ill at Harvey’s apartment, she suggests that they forgo traditional courtship and simply marry.
A week later, after spotting his colleague Toby Radloff dining in his vehicle, Harvey faces the prospect of a new chapter in life as he heads to Delaware to marry Joyce and help her relocate to Cleveland. The real Joyce Brabner then shares her experiences about becoming a character in Harvey’s narratives.
Following their marriage, the couple attends a screening of Revenge of the Nerds with Toby. Harvey finds the film beneath his expectations. When they return to their apartment, a disagreement arises regarding Harvey's belongings, interrupted by a theater producer's interest in adapting American Splendor into a stage play. The play's success in Los Angeles escalates Harvey's fame, even as Joyce grapples with her own emotional turmoil and longings for motherhood. Harvey receives an invitation for a guest appearance on Late Night with David Letterman, where his presence receives enthusiastic responses from the audience, while Toby rises to MTV stardom.
Back in Cleveland, Harvey's newfound recognition revolves more around his Late Night fame than American Splendor, causing frustration. In search of fulfillment, Joyce attends a peace conference without informing Harvey. During her absence, Harvey discovers a lump in his groin.
With Joyce away, Harvey makes a dramatic statement on Late Night by sporting an “On Strike Against NBC” shirt, stirring controversy. Upon Joyce's return, she comes across Harvey's health issue, leading to a lymphoma diagnosis. Although hesitant, she suggests creating a comic about their experience, prompting an artistic intervention with Fred, who illustrates their journey. Along with Fred’s daughter, Danielle, who brings joy to Joyce, Harvey eventually agrees to be a part of the comic.
Harvey undergoes rigorous treatment that tests his physical and mental resilience. He contemplates his existence, questioning whether he is a real person or merely a character in a comic strip, considering the implications of his potential death on the story. Strange visions emerge, as he dreams of numerous Harveys listed in the phone book. A year later, as he and Joyce complete Our Cancer Year, he receives the uplifting news of being cancer-free. The couple adopts Danielle, marking a significant transition into parenthood. The real Harvey retires from the VA hospital, celebrated by the staff with a heartfelt retirement party, where Joyce, Danielle, and Harvey share a touching embrace.
