Cash's parents, Johnny Cash and Vivian Liberto, were married in San Antonio, Texas, in 1954. She has three younger sisters, Kathy, Cindy and Tara. Johnny and Vivian divorced in 1966, and he married June Carter in 1968. Cash's stepsisters are country Singers Carlene Carter and Rosie Nix Adams, also known as Rosey Carter, June Carter's daughters from her first two marriages. Johnny and June's son John Carter Cash is Rosanne's half brother. Cash's stepmother and father died in 2003.

Cash was born in Memphis, Tennessee, in 1955, just as father Johnny was recording his first tracks at Sun Records. The family moved to California in 1958, first to Los Angeles, then Ventura, where Cash and her sisters were raised by mother Vivian. (Vivian and Johnny separated in the early 1960s and divorced in 1966.) After graduating from St. Bonaventure High School, she joined her father's road show for two and a half years, first as a wardrobe assistant, then as a background vocalist and occasional soloist. She made her studio recording debut on Johnny Cash's 1974 album The Junkie and the Juicehead Minus Me, singing lead vocal on a version of Kris Kristofferson's "Broken Freedom Song".

In 1976, Johnny Cash recorded the Rosanne Cash composition "Love Has Lost Again" on his album One Piece At A Time. Though she did not appear on this track, it was Rosanne Cash's first professionally recorded work as a Composer. That same year, she briefly worked for CBS Records in London before returning to Nashville to study English and drama at Vanderbilt University. She then relocated to Los Angeles to study at the Lee Strasberg Theatre Institute in Hollywood. She recorded a demo in January 1978 with Emmylou Harris' songwriter/sideman Rodney Crowell, which led to a full album with German label Ariola Records.

Her self-titled debut album was recorded in 1978, but Ariola never released it in the United States, and it has since become a collector's item. Mainly recorded and produced in Munich, Germany, with German-based Musicians, it also included three tracks recorded in Nashville and produced by Crowell. Though Cash was unhappy with the album, it attracted the attention of Columbia Records, who offered her a recording contract. She began playing with Crowell's band The Cherry Bombs in California clubs. Crowell and Cash married in 1979, and Cash started work on her first Columbia LP.

Cash married country music singer-songwriter Rodney Crowell in 1979. They have three daughters: Caitlin, Chelsea and Carrie. Cash also raised Crowell's daughter, Hannah, from a previous marriage. Cash and Crowell divorced in 1992. She married her second husband, John Leventhal, in 1995, and they have one son, Jakob. Cash lives with her husband and son in Chelsea, Manhattan.

The album, Right or Wrong, was released in early 1980, and produced three Top 25 singles. The first, "No Memories Hangin' Around", a duet with country singer Bobby Bare, reached 17 on the Country Singles chart in 1979. It was followed by "Couldn't Do Nothing Right" and "Take Me, Take Me" in 1980. Cash, pregnant with her first child, was unable to tour in support of the album, which was nevertheless a critical success. Cash and Crowell moved to Nashville in 1981.

Cash's career picked up considerable momentum with the release of her second album, Seven Year Ache, in 1981. The album achieved critical raves and solid sales, and the title track was a No. 1 hit on the Billboard Country Chart, and crossed over to the Billboard Pop Chart, peaking at No. 22. The album yielded two additional No. 1 country hits, "My Baby Thinks He's a Train" and "Blue Moon with Heartache", and was certified Gold by the RIAA.

Cash's third album, Somewhere in the Stars (1982), was considered a disappointment after the commercial success of Seven Year Ache. The album still reached the Top 100 of the U.S. pop album charts, and included three U.S. country chart singles, "Ain't No Money", "I Wonder" and "It Hasn't Happened Yet". Cash struggled with substance abuse during this time, and in 1984 she sought medical treatment.

After a three-year hiatus, Cash released her fourth studio album, Rhythm & Romance (1985), which yielded two No. 1 hits, "I Don't Know Why You Don't Want Me" and "Never Be You", and two other Country Top 10 singles, "Hold On" and "Second to No One". Rhythm & Romance drew high critical praise for its fusion of country and pop. "I Don't Know Why You Don't Want Me" won the 1985 Grammy award for Best Female Country Vocal Performance; "Hold On" won the 1987 Robert J. Burton Award from BMI as the Most Performed Song of the Year.

In the '80s, Cash curtailed her touring for childbearing and raising a family (three daughters with Crowell, as well as Crowell's daughter by his first marriage, Hannah). She continued to record and in 1987 released the most critically acclaimed album of her career, King's Record Shop. It spawned four No. 1 hits, including a cover version of her father's "Tennessee Flat Top Box", John Hiatt's "The Way We Make a Broken Heart", "If You Change Your Mind", John Stewart's "Runaway Train", and became Cash's second gold album. In 1988 Cash recorded a duet with Crowell, "It's Such a Small World" (released on his Diamonds & Dirt album), which also went to No. 1 on the country charts, and Cash was named Billboard's Top Singles Artist of the year.

In 1989, Columbia released her first compilation album, Hits 1979–1989. The album yielded two new hit singles, the Beatles cover "I Don't Want to Spoil the Party", which landed at No. 1 on the Billboard country charts, and "Black and White", which earned Cash her fifth Grammy nomination.

In 1990, Cash released the critically acclaimed, deeply personal Interiors. Cash produced herself for the first time, and wrote or co-wrote all the songs. "Her brutally dark take on intimate relationships was reflected throughout and made clear the marital problems that had been hinted at on earlier albums." "Highly autobiographical (though Cash has often insisted it isn't quite as true to life as everyone assumes), Interiors was a brilliant, introspective album" and "her masterpiece". Other critics called it "maudlin" and "pessimistic". Interiors topped many best album lists in 1990, and received a Grammy award nomination for Best Contemporary Folk Album. It yielded one Top 40 single ("What We Really Want"), and marked the beginning of sharp commercial decline for Cash.

Though it may have been inspired by the breakup of her marriage, it also signified her departure from Nashville and its country music establishment. In 1991 Cash relocated to New York City; in 1992, she and Crowell divorced. The Wheel, released in 1993, was "an unflinchingly confessional examination of the marriage's failure that ranked as her most musically diverse effort to date". The album was Cash's last for Columbia Records. It received considerable acclaim from critics, though neither of its two singles, "The Wheel" or "You Won't Let Me In", charted.

Cash settled in lower Manhattan, and in 1995 married producer/songwriter/guitarist John Leventhal, with whom she had co-produced The Wheel. She signed with Capitol Records, and in 1996 released 10 Song Demo, a collection of stark home recordings with minimal accompaniment. She also pursued a career as a Writer, and in 1996 Hyperion published her short story collection Bodies of Water, to favorable reviews. In 1997, Cash was awarded an honorary doctorate from Memphis College of Art. She gave the commencement address that year and continues to speak publicly on writing and music.

In 1998, she and Leventhal began working on what would later become Rules of Travel. The recording sessions were cut short when she became pregnant and was unable to sing for two and a half years, due to a polyp on her vocal cords.

Unable to record, Cash focused on her writing. Her children's book Penelope Jane: A Fairy's Tale, which included an exclusive CD, was published by Harper Collins in 2000, and in 2001 she edited a collection of short fiction by songwriters titled Songs Without Rhyme: Prose by Celebrated Songwriters. Recovering her voice, she resumed recording and in 2003, released Rules of Travel, her first full-fledged studio album for Capitol. The album had guest appearances by Sheryl Crow and Steve Earle, a song co-written by Joe Henry and Jakob Dylan, and the poignant "September When It Comes," a duet with her father. Rules of Travel was nominated for a 2003 Grammy Award for Best Contemporary Folk Album.

Cash supports several charitable organizations. She is a longtime board member of The Center To Prevent Youth Violence (CPYV), formally known as PAX, an organization dedicating to preventing gun violence among children. She was honored by PAX at their fifth annual benefit gala in 2005.

Cash toured extensively in support of the album, and created a multimedia performance, with video, imagery and narration drawn from the songs and from Cash's family history. In 2006, a short documentary by filmmaker Steve Lippman, "Mariners and Musicians", based on the album and interviews with Cash, premiered at the Tribeca Film Festival and was screened at festivals worldwide. Cash's music was also featured prominently in an American Masters biography of Photographer Annie Leibovitz, who has photographed Cash and her family numerous times.

On November 27, 2007, Cash was admitted to New York's Presbyterian Hospital for brain surgery. In a press statement, she announced that she suffered from Chiari Malformation Type I and expected to "make a full recovery". The surgery was successful, though recovery was slow, and in March 2008 she was forced to cancel her spring tour dates for further recuperation. She wrote about the experience in her New York Times article "Well, Actually, It Is Brain Surgery". She resumed writing, recording and performing in late summer of 2008.

Cash was elected to the Century Association in 2009

Cash wrote New York Times Bestseller Composed: A Memoir in 2010 "a pointillistic memoir about growing up with and without her father, and about how she slid out from under his Shadow to become a gifted Artist in her own right."

She also works with Arkansas State University on the Johnny Cash Boyhood Home project, which is working to restore her father's childhood home in Dyess, Arkansas. The Cash family has supported the restoration by raising money through annual music festivals. Rosanne hosted the first and second annual Johnny Cash Music Festivals in 2011 and 2012.

On February 6, 2012, Cash received the AFTRA Media and Entertainment Excellence Award in Sound Recordings.

Cash gave the closing speech at the Association of Performing Arts Presenters' conference, APAP|NYC, in January 2013.

Cash is a dedicated supporter of artists’ rights in the digital age and sits on the board of the Content Creators Coalition. On June 25, 2014, Cash testified before The House of Representatives, Judiciary Committee on intellectual property rights and Internet music licensing.

In 2015 Cash was inducted into the Nashville Songwriters Hall of Fame, honored as Artist-in-Residence at the Country Hall Music Hall of Fame and Museum, and selected as Carnegie Hall's 2015-2016 Perspective Series Artist.

In 2018, Cash signed with ICM Partners and is working on a new album scheduled for release in the fall.

The River & the Thread is a collection of songs written with husband and collaborator John Leventhal, inspired by trips through the American South. Cash describes The River & The Thread as “a mini-travelogue of the South, and of the soul.” The Journey included visits to father Johnny Cash’s childhood home in Dyess, Arkansas; her own early childhood home in Memphis, TN; william Faulkner’s house, Dockery Farms in Cleveland, MS; the plantation where Howlin’ Wolf and Charley Patton worked and sang; Natchez, MS, the blues trail; the Tallahatchie Bridge; as well as a visit with Natalie Chanin, a master seamstress in Florence, Alabama.