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 while filming the fantasy adventure Willow, and after marriage in 1988 moved to Los Angeles, where she used as her professional name Joanne Whalley-Kilmer. She continued filming, making more films in Hollywood than in the UK, including the mystery noir Shattered and, in 1989, the role of Christine Keeler in Scandal alongside stars John Hurt and Sir Ian McKellen. 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 also starred in the 1997 film The Man Who Knew Too Little.
Whalley met the American actor Val Kilmer while filming the fantasy adventure 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 who was born on 6 June 1995. Shortly after that, the pair separated. Whalley filed for divorce on 21 July 1995, citing irreconcilable differences.
After divorce, Whalley returned to acting through making television films, including the 2000 television film Jackie Bouvier Kennedy Onassis in which she played the title character. She collaborated with the pop-punk band Blink-182 to read 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. The same year she also filmed Played which also starred her ex-husband Val Kilmer but the two did not share any scenes. In 2006, she appeared in Life Line, a two-part drama on BBC1, starring opposite Ray Stevenson. In 2008, she appeared in the ITV mini series Flood with Robert Carlyle amongst others.
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.
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. She shared with the cast of 44 Inch Chest, the Best Ensemble Award at the San Diego Film Critics Society Awards 2010. The film reunited her with John Hurt. She played Aunt Patience in Jamaica Inn for BBC One in 2014. In 2015, she played Claudia, the wife of Pontius Pilate, in A.D. The Bible Continues.
In 2018, she appeared in the third season of Daredevil as Matt Murdock's mother Sister Maggie.