Sofer was born in Arcadia, California, the daughter of Susan (née Franzblau), a psychology professor, and Martin Sofer, a Conservative Jewish rabbi. Her family subsequently moved to Pittsburgh, where she was raised after her parents' divorce. Sofer attended the Frisch School, a Jewish high school in Paramus, New Jersey. She lived in North Bergen, New Jersey, where her father was Rabbi of Temple Beth El, and graduated from North Bergen High School, before beginning classes at Montclair State College.
Sofer first played Lois Marie Cerullo on General Hospital. Her first appearance was in 1993 as a band manager.
Sofer's first high-profile role was as Rocky on the daytime soap opera Loving (1988–91). She is perhaps best known for her role as Lois Cerullo on General Hospital (December 15, 1993 – September 24, 1996). She would later return as a guest star (February 7–17, 1997; September 30-October 2, 1997). Her portrayal of the outrageous Lois won Sofer a Daytime Emmy Award in 1995 for Outstanding Supporting Actress in a Drama Series.
In May 2013, it was announced that Sofer would join the CBS soap opera The Bold and the Beautiful, in a newly created role of Quinn Fuller; her first episode aired on July 12.
Sofer has appeared in several high-profile prime time television series in a guest star/supporting cast member roles: Seinfeld, Melrose Place, The Chronicle, Ed, Friends, Spin City, Blind Justice, Ghost Whisperer, 24, NCIS, and Two and a Half Men.
Sofer briefly joined the cast of the NBC sitcom Just Shoot Me!, playing the character Vicky Costa. The network later cast Sofer in the short-lived US remake of the UK series Coupling.
In recent years, Rena Sofer has appeared in the NBC TV series Heroes as the recurring character Heidi Petrelli, wife of aspiring politician Nathan Petrelli (Adrian Pasdar). She appeared on Two and a Half Men in 2008, as a former girlfriend of the character Charlie Harper (Charlie Sheen). Rena also has guest starred on Dirty Sexy Money playing an intrepid reporter and played a ghost on Ghost Whisperer. In early 2010, Sofer began a recurring role on NCIS as Attorney Margaret Allison Hart, who is a potential love interest for the character Leroy Jethro Gibbs (Mark Harmon). She had a brief guest role on Bones as a love interest for the character Seeley Booth (David Boreanaz).
In 2013, Sofer had a publicized appearance on Once Upon a Time, playing Snow White's mother.
In film, she appeared as a love interest of Ben Stiller's character in the film Keeping the Faith, starring Jenna Elfman, Stiller and Edward Norton (who also directed). She also played a bride to-be with Melanie Griffith in Sidney Lumet's movie A Stranger Among Us and in Penelope Buitenhuis's movie The Secret of Hidden Lake.
She played the P.E. teacher Ms. Desjarden in the television film adaptation of Carrie in 2002.
She starred in the television movie Always and Forever which aired October 24, 2009 on the Hallmark Channel.
She also starred as Andrea Larson in the television movie Saved by the Bell: Hawaiian Style.
Sofer and General Hospital love interest and co-star Wally Kurth became involved as their characters' storyline progressed. In 1995, the actors were married and had a daughter, Rosabel Rosalind Kurth. In 1997, Sofer and Kurth divorced.
Sofer married television director/producer Sanford Bookstaver in 2003. On August 5, 2005, Sofer gave birth to her first child with Bookstaver, named Avalon Leone, in Los Angeles.