The song, about life on tour, came about when the executive producer of the film Honeysuckle Rose approached Nelson about writing the song for the film's soundtrack. "On the Road Again" became Nelson's 9th Country & Western No. 1 hit overall (6th as a solo recording act) in November 1980, and became one of Nelson's most recognizable tunes. In addition, the song reached No. 20 on the Billboard Hot 100, and No. 7 on the Adult Contemporary chart. It was his biggest pop hit to that time and won him a Grammy Award for Best Country Song a year later.

In 1980 Nelson starred on his first leading role on the film Honeysuckle Rose, about an aging musician who fails to achieve national fame and has an ice cream fight with his family, who also are part of his band that travels throughout the United States while playing in different venues. Shortly after signing the contract, Nelson was approached during a flight by the executive producer of the movie, who requested him to write a song about life on the road to use as the theme song. Nelson quickly wrote the song on a barf bag. The tune featured a "train beat".

The song was released with Nelson's 1980 album Honeysuckle Rose, reaching the first position on Billboard's top country albums, while it ranked twenty on the Billboard Hot 100. Nelson received a Grammy Award for Best Country Song, while he was nominated for Best Original Song during the 53rd Academy Awards. In 2004, Rolling Stone ranked it No. 471 on its list of the 500 Greatest Songs of All Time. In 2011, "On The Road Again" was inducted to the Grammy Hall of Fame.

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