She is known for her roles in films including About Last Night (1986), From the Hip (1987), Big (1988), Enid Is Sleeping (1990), The Flintstones (1994), Moonlight and Valentino (1995), The Ring Two (2005) and Hop (2011).

[5] In 1984, she made her theatrical debut on Broadway in Neil Simon's Brighton Beach Memoirs[7] and afterward, worked in a number of ensemble companies, including The New York Shakespeare Festival and the Steppenwolf Theater.

From 2005 to 2009, Perkins played Celia Hodes, an alcoholic and image-obsessed parent–teacher association (PTA) mother, alongside Mary-Louise Parker and Justin Kirk on the Showtime series Weeds.

[5] At a screening of the season 2 finale of Weeds, at the Museum of TV and Radio on October 25, 2006, Perkins said that she considers Celia Hodes her favorite role in her career.

[15] In 2017, Perkins held a sign naming actor James Woods above the hashtag #MeToo during a rally against sexual harassment in Los Angeles.