Her first major film was Jamaica Inn (1938) directed by Alfred Hitchcock. Charles Laughton was so pleased with O'Hara's performance that he cast her in the role of Esmeralda opposite him in The Hunchback of Notre Dame (1939), which was to be filmed at RKO Studios in Hollywood that same year. After the successful completion of Hunchback, World War II began, and Laughton, realizing their studio could no longer film in London, sold O'Hara's contract to RKO. That studio cast her in low-budget films until she was rescued by director John Ford, who cast her as Angharad in How Green Was My Valley, which won the 1941 Academy Award for Best Picture.
Six years later, in 1947, she made what is perhaps her best-remembered film, starring as Doris Walker and the mother of a young Natalie Wood in 20th Century Fox's Miracle on 34th Street, which, despite being released in May, has become a perennial Christmas classic, with a traditional network television airing every Thanksgiving Day on NBC. The film also helped to further establish O'Hara's career after the film garnered several awards, including an Academy Award Nomination for Best Picture.
In 1939, at the age of 19, O'Hara secretly married Englishman George H. Brown, a film producer, production assistant and occasional scriptwriter whose best known work is the first of Margaret Rutherford's 1960s Miss Marple mysteries, Murder She Said. The marriage was annulled in 1941. Later that year, O'Hara married American film director William Houston Price (dialog director in The Hunchback of Notre Dame), but the union ended in 1953, reportedly as a result of his alcohol abuse. They had one child in 1944, a daughter named Bronwyn FitzSimons Price. Bronwyn has one son, Conor Beau FitzSimons, who was born on September 8, 1970. From 1953 until 1967 O'Hara had a relationship with Enrique Parra, a Mexican politician and banker. She wrote in her autobiography ; "Enrique saved me from the darkness of an abusive marriage and brought me back into the warm light of life again. Leaving him was one of the most painful things I have ever had to do."