Panettiere was born in and partly raised in Palisades, New York, the daughter of Lesley R. Vogel, a former soap opera actress, and Alan L. "Skip" Panettiere, a fire department lieutenant. Panettiere is of Italian descent, her surname meaning "baker" in Italian. She has one younger brother, fellow actor Jansen Panettiere.
Although Panettiere attended South Orangetown Middle School in New York, she was educated at home from the 9th grade through high. For now, Panettiere is postponing higher education in favor of an acting career.
Panettiere first appeared in commercials at 11 months, beginning with an advertisement for Playskool. She landed a role as Sarah Roberts on the ABC soap opera One Life to Live (1994–1997), and she followed that up by playing the part of Elizabeth "Lizzie" Spaulding on the CBS soap opera Guiding Light (1997–2000). While on Guiding Light, Panettiere's character Lizzie battled leukemia. For drawing the attention of daytime viewers to the disease, and for improving national awareness, the Leukaemia & Lymphoma Society gave her its Special Recognition Award.
For her performance in Lifetime Television's 1999 TV movie If You Believe, she was nominated for the Young Artist Award for Young Actress Age Ten or Under in the category of Best Performance in a TV Movie or Pilot. Panettiere appeared on Fox's Ally McBeal as the title character's daughter, had a recurring guest role on Malcolm in the Middle and guest starred in Law & Order: Special Victims Unit.
Panettiere became most prominent as Claire Bennet in the NBC series Heroes, which was created by Tim Kring, as a high school cheerleader with regenerative healing powers. Thanks 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 Gen Con, New York Comic-Con, and Fan Expo Canada. Panettiere has complained that her acting options are sometimes limited because "people look at [her] as either the 'popular cheerleader' type or just 'the blonde.'"
In early 2007, Panettiere appeared on the MTV show, Punk'd. The appearance was engineered by her mother and involved a male "fan" discussing her work with her, instigating a jealous reaction from the man's spouse.
Panettiere has appeared in over a dozen full-length feature films.
In 1998, she provided the voice for Dot in A Bug's Life. She played the role of Coach Yoast's daughter, Sheryl, in the 2000 Disney film Remember the Titans. She starred in a 2005 film, Racing Stripes where she plays a teenage girl with a pet Zebra named Stripes. She also starred in Bring It On: All or Nothing as a cheerleader and had a supporting role as Adelaide Bourbon in the recently released independent film Shanghai Kiss. In 2004, she appeared in the Disney Channel film Tiger Cruise, and in Raising Helen as Kate Hudson's adolescent niece. In 2005, she was the title character's rival in a skating contest in Ice Princess.
In June 2007, she signed with the William Morris Agency, after previously being represented by United Talent Agency. Forbes estimated that she earned $2 million in 2007.
In 2008, Panettiere appeared in the drama Fireflies in the Garden as a younger version of Emily Watson's character, Jane Lawrence. In September 2008, she appeared in a satirical video, a mock-PSA (public service announcement) on funnyordie.com entitled "Hayden Panettiere PSA: Your Vote, Your Choice." Again, in October, Panettiere appeared in another satirical PSA video on funnyordie.com entitled "Vote for McCain: He's just like George Bush, except older and with a worse temper."
In July 2009, Panettiere starred in the teen comedy I Love You, Beth Cooper. In September 2010, Panettiere was signed to star as Amanda Knox in the controversial Amanda Knox: Murder on Trial in Italy.
Panettiere also provided the voice of Kate, along side Justin Long in 2010's Alpha and Omega.
In 2011, she replaced Anne Hathaway as the voice of Red for the animated sequel Hoodwinked Too! Hood vs. Evil. In September 2008, Panettiere appeared in the CW's teen series of the A-List franchise, The A-List. She played Delia Young alongside Amber Heard and Amanda Crew.