In 1980, Nile released his self-titled debut album. His early career was interrupted by various problems, but he eventually returned to recording and performing in the US and Europe, establishing himself as a singer-songwriter.
He grew up with two older brothers who played piano, and a mother who "used to always have music in the house. Whether it was classical or big band or popular hits of the times, something was always playing." His grandfather ran an orchestra in Buffalo and was a vaudeville pianist who played with Bill "Bojangles" Robinson and Eddie Cantor.
Nile studied philosophy at the University at Buffalo and lived in Greenwich Village while beginning his music career. He contracted pneumonia and wrote songs while he spent a year recuperating. Afterward, he began frequenting such clubs as CBGB, where he saw performers including Patti Smith, Television, the Ramones, and Talking Heads.
Nile established residency at Kenny's Castaways, a Greenwich Village club, which led to a record deal with Arista Records. He went into the studio with a band that included Jay Dee Daugherty from the Patti Smith Group.
After his second album 1981's Golden Down, Nile became involved with protracted legal problems which curtailed his career for some years.
Although he continued to write, Nile did not perform live or record again until a 1987 performance in Oslo, Norway, with Eric Andersen. A videotape of Nile’s performance in Norway prompted a Columbia talent scout to sign him to the label in 1988. For reasons that are unclear, production on his album didn't start for two more years. It was another significant delay in the troubadour’s career. Issued in 1991, His Columbia Records CD Places I Have Never Been contained the songs "Everybody Needs A Hammer" and "Heaven Help The Lonely." Places I Have Never Been featured appearances by backing musicians including Richard Thompson, Loudon Wainwright III, Roger McGuinn, and members of the Hooters and the Roches. On June 11, 1991, Nile was the guest musician on the Late Night with David Letterman show.
Nile has recorded and performed with several musicians, including Ringo Starr, Tori Amos, Elvis Costello, Lucinda Williams, Ian Hunter, and Barenaked Ladies. A live Central Park concert album, Willie Nile-Archive Alive, was released on Archive Recordings, and Nile was one of the vocalists on the 1998 ensemble album Largo, along with Joan Osborne, Cyndi Lauper, Levon Helm, The Chieftains, Taj Mahal and Carole King. Another project found Nile writing and performing most of the songs for the soundtrack to the Kevin McLaughlin film Pinch Me!.
Gathering together his resources over time, he put out his first self-released album, Beautiful Wreck of the World, in 1999. It was chosen as one of the Top Ten Albums of the Year by critics at Billboard Magazine, The Village Voice and Stereo Review.
Lucinda Williams called "On the Road to Calvary," Nile's song for Jeff Buckley, "One of the most beautiful songs I've ever heard." The album reached the finals of the Independent Music Awards for Best Rock Album of the Year.
In the fall of 2003, Nile was invited to share the stage at three concerts with the E Street Band, including the two final Giants Stadium shows as well as the two last shows of that particular tour at Shea Stadium.
In 2006, Nile released Streets of New York, which some may consider to be his best work to date, due to its production and songwriting. Former Time magazine music critic and Academy Award-winning screenwriter Jay Cocks writes of Streets of New York, "The tunes he writes and plays with such blowtorch vibrancy get the myth and magic and danger and sadness and love in this town--of this town--truer, and righter, than anything I've heard since Dion. This record is a head-twister and heart-wrencher. It's rock and roll at its best. It's New York at its best. And there's nothing better than that."
House Of A Thousand Guitars was released to positive reviews on April 14, 2009.
On April 23, 2013 at a ceremony in Leeds, UK, Nile was named Legacy Ambassador for the Buddy Holly Educational Foundation.
On June 25, 2013, Nile releases his eighth full-length studio album, American Ride through Loud & Proud Records. Nile originally had planned on self-distributing through money raised on PledgeMusic.com. The decision to sign onto a record label occurred after he was approached by Tom Lipsky, president of Loud & Proud Records.
At a surprise appearance at the 2015 Light of Day Benefit in Asbury Park, New Jersey, Bruce Springsteen joined Nile on stage to perform Nile's One Guitar.
 On May 28, 2015, at the Best Buy Theatre in New York City, Nile joined Bruce Springsteen, Joan Jett, Roger Daltrey and Billy Idol at the 11th annual MusiCares MAP Fund benefit concert to honor Pete Townshend for his commitment to helping other musicians with addictions.
Nile was inducted into the Buffalo Music Hall of Fame in 2005.
But, soon after his 1981 album, 'Golden Down,' Nile's career was put on hold, due to music business legal issues that derailed his career for a decade.