His first song credit is listed as "In Love with the Memory of You", with music by William Schuman, published in 1931. Loesser's early lyrics included two hit songs of 1934, "Junk Man" and "I Wish I Were Twins" (both with music by Joe Meyer, and the latter with co-lyric credit to Eddie DeLange). However, they apparently did not help his reputation, and in later years, he never mentioned them. After signing a six-month contract with Universal Pictures, in 1936 he moved to Hollywood with his new wife. After his contract was up, he was offered another contract by Paramount Pictures. His first song credit with Paramount was "Moon of Manakoora" written with Alfred Newman for Dorothy Lamour in the film The Hurricane. He stayed in Hollywood until World War II when he enlisted into the Air Force. In 1948, he sold the rights to a song he wrote in 1944 and performed informally at parties with his then wife Lynn Garland to MGM. The studio included in the 1949 movie Neptune's Daughter, and the song, Baby, It's Cold Outside became a huge hit. Garland was mad at Loesser for selling what she considered "their song" to MGM. He ended up winning the Academy Award for Best Original Song for the song.
After working on the film Neptune's Daughter, he wished to write more than one song for a film. His wish was granted in 1952 when he wrote the music and lyrics for the film Hans Christian Andersen. The movie had notable songs such as "Wonderful Copenhagen", "Anywhere I Wander", "Thumbelina", and "Inchworm". He wrote the book, music and lyrics for his next two musicals, The Most Happy Fella (1956) and Greenwillow (1960).
In 1956, Lynn and Loesser got divorced, and Loesser then began a relationship with Jo Sullivan, who had a leading role in Fella. He wrote the music and lyrics for How to Succeed in Business Without Really Trying (1961), which ran for 1,417 performances and won the 1962 Pulitzer Prize for Drama and for which he received two more Tonys. The last musical of his that was produced, Pleasures and Palaces (1965), closed during out-of-town tryouts. At the time of his death he was working on Señor Discretion Himself, for which he was writing the book, music and lyrics.