Perhaps taking up the role of Carla Bley as Mantler's preferred "musical" pianist, Karen participated in the recording of his Folly Seeing All This (where she also contributes a vocal counterpart to Jack Bruce), and was next featured as a singer on the recording and in performances of The School of Understanding.

Daughter of Michael Mantler and Carla Bley, she started performing at a very early age. Her first singing appearance was in 1970 on Carla Bley's Escalator Over The Hill at the age of four, and again three years later on Tropic Appetites. She then played glockenspiel in the Carla Bley Band and appeared on the album Musique Mecanique. After attending Berklee College of Music in Boston she went on to form her own band which performed in the USA as well as in Europe and recorded two albums for ECM/XtraWATT (My Cat Arnold and Get The Flu). She rejoined the Very Big Carla Bley Band as the organ and harmonica player, touring and recording, and also appeared on recordings by Steve Weisberg, Motohiko Hino, Steve Swallow and Robbie Dupree.

In 1996 she recorded a third album of her own compositions called Farewell, again for ECM/XtraWATT, and she also toured Europe as a Duo with drummer Michael Evans. In 1997 she appeared as a singer and keyboard player in a series of performances of Carla Bley's Escalator Over The Hill in Cologne, and again for a European tour in 1998.

Another CD of her own compositions called Karen Mantler's Pet Project, was released by Virgin Classics in 2000. Most recently she has collaborated with John Greaves (both recording and with his Dondestan live project) and with Robert Wyatt, contributing songs and appearing on his Cuckooland CD.