在2000年之后，Cash的身体状况更加不容乐观，但他并没有放下毕生热爱的音乐。他与Rick Rubin合作的第四张专辑《American IV: The Man Comes Around》最终在2002年11月面世。
American IV: The Man Comes Around is the fourth album in the American series by Johnny Cash, released in 2002. The majority of songs are covers which Cash performs in his own sparse style, with help from producer Rick Rubin. For instance, for the song "Personal Jesus", Rubin asked Red Hot Chili Peppers guitarist John Frusciante to re-work an acoustic version of Martin Gore's song, which featured a simple acoustic riff that stripped down the song to a blues style. He receives backing vocal assistance from various artists, including Fiona Apple, Nick Cave, and Don Henley. American IV was the last album released by Cash during his lifetime. It was also his first album to go gold (selling over 500,000 copies) in thirty years.
The video for "Hurt", a song written by Trent Reznor of Nine Inch Nails in 1994, was nominated in seven categories at the 2003 MTV Video Music Awards and won the award for Best Cinematography. In February 2003, mere days before his 71st birthday, Cash won another Grammy Award for Best Country Male Vocal Performance for "Give My Love To Rose," a song Cash had originally recorded in the late 1950s. The music video for "Hurt" also won a Grammy for Best Short Form Video at the 2004 Awards.
Nine Inch Nails frontman Trent Reznor admitted that he was initially "flattered" but worried that "the idea (of Cash covering "Hurt") sounded a bit gimmicky," but when he heard the song and saw the video for the first time, Reznor said he was deeply moved and found Cash's cover beautiful and meaningful. He later said in an interview, "I just lost my girlfriend, because that song isn't mine anymore.