Smith was born in Red Bank, New Jersey, the daughter of filmmaker Kevin Smith and actress Jennifer Schwalbach Smith. She was named after the Batman villain Harley Quinn. She is a good friend and frequent co-star of Lily-Rose Depp, daughter of actor Johnny Depp.
Smith made her acting debut in her father's film Jay and Silent Bob Strike Back, by portraying the elder Smith's usual character, Silent Bob, as a child. In 2004, she had an uncredited cameo as Tracy Colelli in the drama film Jersey Girl and two years later in the comedy film Clerks II. In 2014, she had a small role in the thriller film Tusk, a role she reprised in 2016's Yoga Hosers. In January 2016, it was announced that Smith will play her father's character's daughter in the half-hour comedy Hollyweed.
|2001||Jay and Silent Bob Strike Back||Baby Silent Bob|
|2004||Jersey Girl||Tracy Colelli||Uncredited|
|2006||Clerks II||Kid in Window|
|2016||Yoga Hosers||Colleen McKenzie|
|2014||Comic Book Men||Herself||1 episode|
|2017||Supergirl||Izzy Williams||Episode: "Supergirl Lives"|
|2017||Big Hero 6: The Series||Jodie Fischer||Voice role|