In 1937, sportscaster Reagan convinced his boss at the WHO Des Moines radio station to send him to Los Angeles to cover the Chicago Cubs's spring training games. Reagan's ulterior motive, however, was to see if he could make it in the motion picture industry. He had fond memories of his high school and college acting days, and when several of his friends at the radio station had been signed by the movie studios, he decided that he too could become a professional actor.

Entering the business wasn't easy. In order to make it in Hollywood, one had to have an agent and a more professional background in acting than simply high school plays. He eventually did find an agent–John Meiklejohn–in Los Angeles, but he had to lie about his former acting experiences to make Meiklejohn think Reagan was actually a professional actor. Meiklejohn paraded the aspiring actor around several studios where directors and producers would meticulously scrutinize Reagan's body, hair, eyes, voice, mouth, and everything else that could possibly appear on screen. After a particularly grueling screen test at the Warner Brothers studio, WB told Dutch Reagan to wait around a few days for another screen test. Surprisingly, Dutch told them no, that he had to be back in Des Moines by that time to begin covering the regular season Cubs games. He left the studio feeling a fool for having said no to a possible movie career, and arrived in Des Moines feeling even worse. Within days, however, he received a telegram from Meiklejohn saying that Warner Brothers was offering him a one-year contract with a starting salary of $200 per week. Reagan, the twenty- six year old radio announcer, quickly accepted.

Ironically, Reagan didn't have to act much in his first film, Love is in the Air, because he played the role of a radio announcer. Over the year, he played only slightly better characters. More often than not, he played the supporting actor to the lead. Reagan was also only featured in B movies. At the time, most theatres showed double features; moviegoers primarily paid to see the A picture that starred famous actors, but were also shown a B feature as well. As a result, B films were generally low budget, hastily made, and poorly acted. Reagan didn't mind, though. He was earning good money, working in Hollywood, and realized that every actor had to start at the bottom in order to become famous. He had the opportunity to date other movie stars, and was usually followed by a photographer or two. By 1938, he bought a house in Los Angeles for his parents, as well. During his first year in Hollywood, he made eight films, and he made another eight films his second year.

In 1938, while on the set of Brother Rat, Reagan met actress Jane Wyman who would later be famous for her roles in popular movies such as The Yearling, Pollyanna, and Johnny Belinda for which she received an Academy Award for best actress. Immediately, fans latched on to gossip about a possible romance, and soon Reagan and Wyman had become the couple in Hollywood. The two toured parts of the country together–including Dixon, Illinois–as part of a showcase of stars, and eventually announced their engagement. They were married on January 26, 1940, in Glendale, California, and honeymooned in Palm Springs. The couple had three children together: Maureen born in 1941, Michael adopted in 1945, and a baby girl who died shortly after her premature birth in 1947. The death of the baby traumatized Wyman, and she and Reagan separated and divorced the next year. Wyman took custody of their two children, but Reagan remained close to them all his life. In his autobiography, An American Life, Reagan only mentions his marriage to Jane Wyman in a two-sentence paragraph.

In 1940, Reagan got the idea to write his own screenplay for a film about Knute Rockne, the legendary football coach at the University of Notre Dame who revolutionized the game of football. A former football player himself, Reagan wanted to act the part of the inspirational Notre Dame player George Gipp in the movie. To sell his idea, he took the ideas for the screenplay to his bosses at Warner Brothers, but he was disappointed they turned him down. Surprisingly, he read in a magazine some time later that Warner Brothers would soon begin production on a new movie–about Knute Rockne! He raced down to the studio to audition for the part of Gipp, but was told that he was too small for the part. He pleaded with the producer, showed him a photograph of himself in his old high school football uniform, and won the part. Although he wasn't in much of the finished production, Knute Rockne, All American, his A movie acting premiere did win him acclaim and boosted him to stardom.

Then, in 1941, Ronald Reagan starred in the movie King's Row in which he played a man who wakes up in the hospital only to discover that his legs have been amputated by a vengeful doctor. The hospital scene was particularly emotional when Reagan cried out, "Where's the rest of me?", and for a while there was rumor that his performance might even win him an Academy Award. Although he lost the Oscar to actor Jimmy Cagney, he always considered this role to be his finest. Needless to say, so did his producers and the majority of his fans in Hollywood. Reagan had become an American superstar. By now he was earning over $100,000 a year.

Ironically, at the pinnacle of his success in Hollywood, Reagan had to stop making movies. Merely several months after the bombing of Pearl Harbor in December of 1941, the famous actor and future President received his notice from the US Army instructing him to report for duty in San Francisco. Because Reagan's eyesight was horrible (he was among the first Americans to wear experimental contact lenses), he was assigned to logistics duty in the US. Then, in mid-1942 he was transferred to Fort Roach in Los Angeles to join the newly-formed First Motion Picture Unit within the Army Air Corp's intelligence department. With a lieutenant's commission, Reagan recruited several of his contacts in the motion picture industry to join the army and make military movies with him.

Most of the films Reagan made during the war were classified and made for US military pilots conducting bombing raids in Japan and the Pacific. He also made training films for new recruits. As a member of Army Intelligence, Reagan often knew of bombing raids before they occurred. He also handled and documented much of the films taken on the battlefield in Europe and Japan, as well as enemy films intercepted by the US Army. He was among the first Americans to ever witness footage of the horrors of the Holocaust. He was horrified by the images he saw, and never forgot them. Reagan based many of his policies decades later on the premise of preventing such horrible atrocities from ever happening again. He returned to Hollywood and filmmaking in 1946.