Appleby began her acting career at the age of four, starting with advertisements for various products such as Cheerios and M&M's. Her first advertisement was for Raisin Bran but it was never aired. She made 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 (1997), Beverly Hills, 90210 (1990), before landing her break-out role in the series Roswell (1999-2002), for which she tried out for the roles of both Isabel and Maria before landing the leading role of Liz Parker.
Appleby also featured in a number of music videos, such as Bon Jovi's video for "It's My Life" with Will Estes, and the 2004 video for the song "I Don't Want To Be" by Gavin DeGraw, opposite Scott Mechlowicz. She also appeared in Sense Field's music video for "Save Yourself" which is part of the Roswell soundtrack and featured in the first season DVD boxset.
In 2006, she took a recurring role on the short-lived ABC drama Six Degrees as Anya, a young assistant in a relationship with a much older photographer. Later that year she was chosen to play Hildy Young in the new USA Network series To Love and Die, that began airing in late December 2008. She also participated in a short film called Carjacking directed by Dan Passman and co-starring Geoff Stults.
In 2007, she appeared in the movie What Love Is alongside Cuba Gooding Jr., Matthew Lillard and Anne Heche. She also participated in another short film, Love Like Wind, from Shaolin Film Productions. At the end the year, she appeared as Charlie Wilson's press secretary in the film Charlie Wilson's War, which stars Tom Hanks and Julia Roberts. In 2008, Appleby got a recurring role on the 15th and final season of ER, being her second time on the show, playing an intern named Daria Wade.
Appleby then starred in The CW network drama; Life Unexpected as Cate Cassidy, a radio talk show host whose daughter gets back into her life. The show was cancelled after two seasons. In the summer of 2012 she starred as the main character of "Dating Rules from my Future Self".