Miller was born in Manhattan and attended the Convent of the Sacred Heart. She is the daughter of Bonnie Trompeter and the niece of Actress Susan Saint James and NBC Sports executive Dick Ebersol. She has a sister and one brother, John. Miller was a model as a child, appearing in a Wonder Bread commercial when she was six months old, posing at three for Francesco Scavullo in an Ivory soap advertisement, and being photographed for the cover of Redbook. Her days as a child model were curtailed after an operation for a benign bone tumor. After attending Convent of the Sacred Heart, she returned briefly to modeling, but soon took acting lessons, and gave up modeling when she moved to Los Angeles, California, in 1990. She was cover model and had a pictorial in the first U.S. edition of Maxim.

Miller's first role on television was in Kate & Allie, which starred her real-life aunt, Susan Saint James, whom she resembles. She then appeared in episodes of Northern Exposure, Fresh Prince of Bel Air, and Party of Five. She had a small role in the horror film Stepfather III (1992) with Priscilla Barnes. Miller later appeared twice on Seinfeld, as two different characters. In the 1993 episode "The Sniffing Accountant", she played the boss of George Costanza. She had intended to be a dramatic Actress, and this role proved to be a turning point for Miller, who realized how much she enjoyed comedy. Two years later, she returned to Seinfeld in "The Doodle" to play George's girlfriend, Paula. This episode proved to be a boon to her career, as she convinced co-creator Larry David to provide her with a rough-cut video of the still-unaired episode when she auditioned for The Drew Carey Show, whose producers had initially thought she was too inexperienced. David's support helped Miller win over the producers of The Drew Carey Show, who cast her as Kate O'Brien, whom she played from 1995 to 2002.

Miller married Bill Lawrence in 1999. They have three children, Charlotte Sarah (born June 8, 2000), william Stoddard (born January 3, 2003), and Henry Vanduzer (born October 8, 2006). Her last two pregnancies were written into Scrubs.

In 2001, Miller's husband, writer-producer Bill Lawrence, conceived a new comedy-drama, Scrubs. Miller was given a guest role as Dr. Cox's (John C. McGinley) acerbic ex-wife Jordan Sullivan. Originally, the character was intended to appear in only one episode; in season 2, the role became recurring. When her young cousin Teddy Ebersol, son of Susan St. James and Dick Ebersol, died in a plane crash in 2004, Scrubs dedicated the season-4 episode "My Lucky Charm" to him. Miller also was the voice of Cleopatra in the short-lived animated show Clone High. She had a leading role in the 2008 two-part TV miniseries The Andromeda Strain. She also appeared in the CSI: Miami episode Divorce Party .

In 2009, Miller began starring on Cougar Town, a sitcom created and produced by her husband and starring Courteney Cox, with whom Miller worked in a three-part story-arc of season 8 of Scrubs.