She began her career at age 12 as a print model. During her early teen years she appeared in television commercials, and was frequently seen in national print ads like the Sears catalog and Bradlees weekly flyers. In 1979, she received her first recognizable national television exposure playing a cheerleader with a cast on her leg in a TaB Cola commercial. At the age of 15, Loughlin was cast on ABC's soap opera The Edge of Night, playing the part of Jody Travis, an aspiring dancer. After three-and-a-half years, prompted by the urging of Joel Crothers, Loughlin decided to try her luck in feature films and television. Her big break came when she was cast on the sitcom Full House playing the role of Rebecca Donaldson, which would be her most notable role to date.

After Full House, she starred alongside Bruce Campbell in In the Line of Duty: Blaze of Glory, which was released in 1997. In 2000, Loughlin co-starred opposite Treat Williams in the Fred Olen Ray-helmed thriller Critical Mass. She also made cameos on other sitcoms including Spin City, Seinfeld, and The Drew Carey Show. She also played the superhero Black Canary in the short lived Birds of Prey series.

From 2004 to 2005, Loughlin co-created, produced and starred in the WB drama series Summerland. She played Ava, the aunt who raises three children after their parents die in a car accident. The series was cancelled due to low ratings on July 11, 2005. Loughlin starred on the ABC sitcom In Case of Emergency with David Arquette. She appeared in the film Moondance Alexander, co-starring Kay Panabaker. She currently stars in the Beverly Hills, 90210 spinoff 90210 as Debbie Wilson. Loughlin was in attendance at Comedy Central's The Roast of Bob Saget which was hosted by John Stamos, and premiered on August 17, 2008. At her table were Full House co-stars Dave Coulier and Jodie Sweetin.

• Old Dogs (2009/I) (completed)
  
• "90210" .... Debbie Wilson (12 episodes, 2008-2009)
       - Hello, Goodbye, Amen (2009) TV episode .... Debbie Wilson
       - That Which We Destroy (2008) TV episode .... Debbie Wilson
       - Games People Play (2008) TV episode .... Debbie Wilson
       - Secrets and Lies (2008) TV episode .... Debbie Wilson
       - There's No Place Like Homecoming (2008) TV episode .... Debbie Wilson
        (7 more)
• Moondance Alexander (2007) .... Gelsey
• "In Case of Emergency" .... Dr. Joanna Lupone / ... (13 episodes, 2007)
       - The Picture (2007) TV episode .... Dr. Joanna Lupone
       - Disorder in the Court (2007) TV episode .... Dr. Joanna Lupone
       - Happy Endings (2007) TV episode .... Dr. Joanna Lupone
       - The Good, the Bad and the Mob (2007) TV episode .... Dr. Joanna Lupone
       - Your Goose Is Cooked (2007) TV episode .... Dr. Joanna Lupone
        (8 more)
• "Ghost Whisperer" .... Christine Greene (1 episode, 2006)
       - Demon Child (2006) TV episode .... Christine Greene
• Farce of the Penguins (2006) (V) (voice) .... Melvin-Smacking Penguin
• "Jake in Progress" .... Lindsay (1 episode, 2006)
       - The Two Jakes (2006) TV episode .... Lindsay
• "Summerland" .... Ava Gregory (26 episodes, 2004-2005)
       - What's Past Is Prologue (2005) TV episode .... Ava Gregory
       - Careful What You Wish For (2005) TV episode .... Ava Gregory
       - Safe House (2005) TV episode .... Ava Gregory
       - Space Between Us (2005) TV episode .... Ava Gregory
       - Signs (2005) TV episode .... Ava Gregory
        (21 more)
• "1-800-Missing" .... Dr. Joy Gribben (2 episodes, 2005)
  ... aka Missing (UK) (USA: second season title)
  ... aka Porté disparu (Canada: French title)
       - Anything for the Baby: Part 2 (2005) TV episode .... Dr. Joy Gribben
       - Anything for the Baby: Part 1 (2005) TV episode .... Dr. Joy Gribben
• "Justice League" .... Dr. Tracy Simmons (1 episode, 2004)
  ... aka JL (USA: promotional abbreviation)
  ... aka Justice League Unlimited (USA: third season title)
       - The Greatest Story Never Told (2004) TV episode (voice) .... Dr. Tracy Simmons