After appearing with
Ramón Novarro in
The Barbarian (1933), Loy landed the part that established her as a major actress,
Nora Charles in
The Thin Man (1934). The director
W. S. Van Dyke chose Loy after he realized that she possessed a wit and sense of humor that had not been displayed in her previous films. At a Hollywood party, he pushed her into a swimming pool to test her reaction, and felt that her aplomb in handling the situation was exactly what he envisioned for Nora.
Louis B. Mayer at first refused to allow Loy to play the part, saying that she was a dramatic actress only, but Van Dyke insisted. Mayer relented on the condition that filming be completed within three weeks as Loy was committed to start filming
Stamboul Quest (1934).
The Thin Man became one of the year's biggest hits, and was nominated for an
Academy Award for Best Picture. Loy received excellent reviews and was acclaimed for her comedic skills. She and her costar
William Powell proved to be a popular screen couple and appeared in 14 films together, the most prolific pairing in
Hollywood history. Loy later referred to
The Thin Man as the film "that finally made me... after more than 80 films".
Her success in
Manhattan Melodrama and
The Thin Man marked a turning point in her career and she was cast in more important pictures, and was given the opportunity to develop her comedic skills in films such as
Wife vs. Secretary (1936) with
Clark Gable and
Jean Harlow and
Petticoat Fever (1936) with
Robert Montgomery. She made four films in close succession with William Powell:
Libeled Lady (1936), which also starred
Spencer Tracy and Jean Harlow,
The Great Ziegfeld (1936), in which she played
Billie Burke opposite Powell's
Florenz Ziegfeld, the second "Thin Man" film,
After the Thin Man, and the romantic comedy
Double Wedding (1937). She also made three more films with
Clark Gable. Parnell was an historical drama and one of the most poorly received films of either Loy's or Gable's career, but their other pairings in
Test Pilot and
Too Hot to Handle (both 1938) were successes.
During this period, Loy was one of Hollywood's busiest and highest paid actresses, and in 1937 and 1938 she was listed in the annual "Quigley Poll of the Top Ten Money Making Stars", which was compiled from the votes of movie exhibitors throughout the U.S. for the stars that had generated the most revenue in their theaters over the previous year.
By this time Loy was highly regarded for her performances in romantic comedies and she was anxious to demonstrate her dramatic ability, and was cast in the lead female role in
The Rains Came (1939) opposite
Tyrone Power. She filmed
Third Finger, Left Hand (1940) with
Melvyn Douglas and appeared in
I Love You Again (1940),
Love Crazy (1941) and
Shadow of the Thin Man (1941), all with William Powell.
With the outbreak of
World War II, she all but abandoned her acting career to focus on the war effort and worked closely with the
Red Cross. She was so fiercely outspoken against
Adolf Hitler that her name appeared on his
blacklist. She helped run a Naval Auxiliary
Canteen and toured frequently to raise funds.