Apatow first appeared in the 2007 comedy film Knocked Up, written, produced and directed by her Father Judd Apatow. She plays Sadie to parents Pete (played by Paul Rudd) and Debbie (played by her real life mother, Leslie Mann). Her sister in the film, Charlotte, is played by her real-life sister, Iris Apatow. In 2009, she played Mable, again the daughter to her real-life mother's character, in Funny People, another film her Father wrote, produced and directed. She reprised her role of Sadie in the spin-off to Knocked Up, the 2012 film This Is 40.
In 2013, her Twitter feed was voted as one of the "Best Twitter Feeds of 2013" by Time (magazine), calling her tweets "funny and earnest".
In 2017, she appeared in commercials for Jergens Skin Care Products with her mother.