In April 1982, Webb joined Forbidden Broadway, an Off-Broadway revue parodying musical theatre, particularly Broadway musicals. Four years later, she made her film debut in Alex Cox’s Sid & Nancy (1986); she portrayed the infamous, heroin-addicted Nancy Spungen, girlfriend of punk rock singer Sid Vicious. Her performance garnered best actress awards from the National Society of Film Critics, the Boston Film Critics and the San Francisco Film Critics.

Webb co-starred alongside Denzel Washington and Bob Hoskins in Heart Condition (1990). In 1991, she played a hairdresser in Queens Logic and a woman with a developmental disability who wins the lottery in ABC’s made-for-TV film Lucky Day.

Webb has appeared on several television series: CBS’s Judging Amy (2003), FOX’s House (2005), CBS’s Two and a Half Men (2005), NBC’s Medium (2005), and CBS’s CSI: Crime Scene Investigation (2008). Webb reunited with Cox in 2009 for his film Repo Chick; she played Sister Duncan.