In the post-punk era, she flirted with the fringes of the Manchester New Wave scene and was briefly a member of a Stockport-based band called the Slowguns, but left before the release of their two singles. Later, she was the lead singer of the pop group Cindy & The Saffrons; they recorded the Shangri-Las’ song “Past, Present and Future” in 1982 at Abbey Road Studios and the next year they recorded “Terry” by Twinkle. The group split up soon afterward. In 2003, Whalley appeared on Blink-182’s song “Stockholm Syndrome”, reading letters between Mark Hoppus’ grandparents.

In 1982, she played Ingrid Rothwell in A Kind of Loving, a well-received Granada TV adaptation of Stan Barstow’s three Vic Brown novels. Whalley acted in the film No Surrender (Dumbarton Films with Film Four) scripted by Alan Bleasdale, released in 1985, but the film was not successful.

Whalley came to prominence on British television as Emma Craven in Troy Kennedy Martin’s Edge of Darkness (1985), then as Nurse Mills in the Dennis Potter-written serial The Singing Detective (1986)—both for BBC Television. In 1987 she played Jackie in the TV film Will You Love Me Tomorrow; she also played a role in The Good Father (1985), another Channel 4-backed film.

Whalley met the American actor Val Kilmer in 1987 while filming the fantasy adventure Willow,. After their marriage in 1988, she moved to Los Angeles and began using ‘Joanne Whalley-Kilmer’ as her professional SAG-AFTRA name. She continued filming, making more films in Hollywood than in the UK. In 1989,Whalley-Kilmer played the role of Christine Keeler in Scandal alongside stars John Hurt and Sir Ian McKellen. In 1991 she starred in the mystery noir Shattered.

Whalley met the American actor Val Kilmer while filming the movie Willow. The couple married in 1988. Whalley took a break from filming to bring up her two children with Kilmer. Mercedes was born on 29 October 1991 in Santa Fe, New Mexico, and her son Jack was born on 6 June 1995. Shortly after that, the pair separated. Whalley filed for divorce on 21 July 1995, citing irreconcilable differences.

In 1994, she was the lead actress in Trial By Jury, with co-stars Armand Assante and William Hurt, among others. Also in 1994, she became the second actress to play Gone with the Wind heroine Scarlett O’Hara when she appeared in a made-for-TV adaptation of the sequel novel, Scarlett. She later starred in the 1997 film The Man Who Knew Too Little.

After her divorce from Kilmer in 1996, for personal and professional reasons, she changed her surname back to Whalley. Whalley played the title character in the 2000 television film Jackie Bouvier Kennedy Onassis. She later collaborated with the pop-punk band Blink-182, reading a letter at the beginning of the song “Stockholm Syndrome”. In 2005, she appeared as Queen Mary I in The Virgin Queen, a BBC serial about the life of Queen Elizabeth I which also starred Anne-Marie Duff and Tara FitzGerald. That same year she filmed Played which also starred her ex-husband Val Kilmer. However, the two did not share any scenes together. In 2006, she appeared in Life Line, a two-part drama on BBC1, starring opposite Ray Stevenson.

In February 2008, she appeared on stage in Billy Roche’s Poor Beast in the Rain presented by the Salem K. Theatre Company at the Matrix Theatre, Los Angeles, California. In that same year, Whalley was also a regular in the ITV mini series Flood with Robert Carlyle amongst others.

In 2011, Whalley played one of the female leads, Vannozza dei Cattanei, mistress of Cardinal Rodrigo Borgia, future Pope Alexander VI, in the Showtime historical drama The Borgias. She guest-starred as Princess Sophie in season 4 of Gossip Girl. With the cast of 44 Inch Chest, she shared the Best Ensemble Award at the San Diego Film Critics Society Awards 2010. The film reunited her with John Hurt, with whom she had done two previous films. In 2014 she played Aunt Patience in Jamaica Inn for BBC One. In 2015, she played Claudia, the wife of Pontius Pilate, in A.D. The Bible Continues, and Queen Catherine of Aragon in the BBC miniseries Wolf Hall.

In 2018, she appeared in the third season of Daredevil as Sister Maggie.

In 2020, Whalley starred in the Eleanor Coppola film Love Is Love Is Love. It was scheduled to have its world premiere at the Tribeca Film Festival in April 2020, but the festival was postponed due to the COVID-19 pandemic. The film is rescheduled for its world premiere at the Deauville American Film Festival in September.