She first achieved recognition as an adolescent, portraying Barbara Cooper Royer on the sitcom One Day at a Time (1975–1984), for which she won two Golden Globe Awards for Best Supporting Actress in a Series, Miniseries or Television Film.

She subsequently earned adult stardom as Gloria on the religious drama series Touched by an Angel (2001–2003), and Melanie Moretti on the sitcom Hot in Cleveland (2010–2015), which brought her a Screen Actors Guild Award nomination.

In the 2005 One Day at a Time Reunion Special, she was reunited with cast members Bonnie Franklin, Mackenzie Phillips and Pat Harrington Jr. to watch memorable clips from the show's nine seasons.

After One Day at a Time, Bertinelli starred in several TV films and miniseries and made many guest appearances on other television shows.

In the 1990s, she starred in two short-lived sitcoms: Sydney, as the title character, a private detective (with Matthew Perry and Craig Bierko); and Café Americain.

[9] The following year, she released the autobiography, Losing It: And Gaining My Life Back One Pound at a Time,[10] which culminates in a description of her Jenny Craig diet experience.

In 2015, Bertinelli began hosting Valerie's Home Cooking, and Kids Baking Championship with cake artist Duff Goldman on the Food Network.

In June 2021, it was announced that Bertinelli would star opposite Demi Lovato in NBC's single-camera comedy pilot, Hungry.

[21] In her autobiography, Bertinelli wrote that the main reasons for her divorce were her husband's cocaine addiction, and his refusal to quit smoking despite being diagnosed with oral cancer and losing one-third of his tongue in the treatment process.

[25] Bertinelli ran in the April 2010 Boston Marathon to benefit the Dana–Farber Cancer Institute, completing it in a time of 5:14:37.