Appleby and her younger brother, Evan, were raised in the San Fernando Valley (northwest of downtown Los Angeles, over the Hollywood Hills, in Los Angeles County). Her father, Jerry Appleby, is a Jewish American telecommunications executive and her mother, Dina Bouader, is an Israeli-born school teacher. Shiri has brown eyes, brown hair and is around 5'3" tall. She has a scar above her left eyebrow, resulting from a dog bite when she was young.

She graduated from Calabasas High School (Calabasas, California) in 1996 and went on to major in English literature at the University of Southern California while also studying theater arts. She is known for her work in the community and active participation in charity events.

Appleby began her acting career at the age of four, starting with advertising for various products such as Cheerios and M&M's. Her first advertisement was for Raisin Bran but it was never aired. She has had guest appearances on many television programs, most notably thirtysomething (1987), Doogie Howser, M.D. (1989), ER (1994), Baywatch (1989), Xena: Warrior Princess (1995), 7th Heaven (1996) and Beverly Hills 90210 (1990). For Roswell, she tried out for the roles of both Isabel and Maria before landing the role of Liz Parker. She has also had minor roles in a significant number of movies before Roswell.