Hayden Leslie Panettiere began modeling at the age of five months. She then began appearing in commercials at 11 months, first appearing in an advertisement for Playskool. She landed a role as Sarah Roberts on the ABC soap opera One Life to Live (1994- 1997) and later as Lizzie Spaulding on the CBS soap opera Guiding Light when she was seven years old (1996 - 2000). While on Guiding Light, Panettiere’s character Lizzie battled leukemia. The show received a Special Recognition Award from the Leukemia and Lymphoma Society for bringing national awareness of the disease to the attention of daytime viewers.

Panettiere appears as Claire Bennet in the NBC series Heroes as a high school cheerleader with regenerative healing powers. Due to her role on Heroes, she became a regular on the science fiction convention circuit, invited to attend conventions around the world in 2007, including GenCon, New York Comic-Con and Fan Expo Canada. In regard to the roles she has played, Panettiere admitted that options are sometimes limited because "people look at [her] as either the ‘popular cheerleader’ type or just ‘the blonde’."