She is the elder daughter of Layne Ann (née Wingate), a homemaker, and Gary Carmine Cuoco, a real estate agent.

[5] Her sister, Briana, is an actress and singer who competed on the fifth season of The Voice who co-starred with her on the HBO Max series The Flight Attendant[6] and on Harley Quinn as Barbara Gordon/Batgirl.

[8] Cuoco made her first feature film appearance as the young Karin Carter in the 1995 action thriller Virtuosity.

[citation needed] In September 2007, Cuoco began starring in the CBS sitcom The Big Bang Theory, playing Penny, a Cheesecake Factory employee and aspiring actress who lives across the hall from physicists Dr. Leonard Hofstadter and Dr. Sheldon Cooper.

[11] As of August 2014, Cuoco and her co-stars from The Big Bang Theory Johnny Galecki and Jim Parsons each earned an estimated US$1 million per episode.

[12][13] In late October 2012, Cuoco enlisted the help of her sister Briana to organize a flash mob on the set of the show, in which she and the cast and crew surprised the studio audience by suddenly lip syncing and dancing to Carly Rae Jepsen's song "Call Me Maybe".

[17] She played a minor role in the Prison Break episodes "The Message" and "Chicago", as well as starring in the comedy horror spoof Killer Movie in 2008.

Her first project through Yes, Norman was an adaptation of the book The Flight Attendant, written by author Chris Bohjalian, which was developed into a comedy-drama series of the same name.

[24] The Flight Attendant premiered on November 26, 2020, on WarnerMedia's streaming platform HBO Max to widespread critical acclaim, and was renewed for a second season on December 18, 2020.

[25][26][27] In October 2018, it was announced that Cuoco would voice the title character of the DC Universe adult animation series Harley Quinn, and also serve as executive producer.

[31] In April 2020, Cuoco joined the cast of the upcoming action comedy film The Man from Toronto as the female lead alongside Kevin Hart and Woody Harrelson.

[34] While working on The Big Bang Theory, Cuoco privately dated co-star Johnny Galecki for roughly two years, until December 2009.

[35] On September 13, 2010, Cuoco broke her leg in a horse-riding accident and missed the filming of two episodes of The Big Bang Theory.