Zareen Khan's acting career began while visiting the set of Yuvraj at Subhash Ghai's film school Whistling Woods. Salman Khan noticed her and decided to cast her for his friend Anil Sharma's film Veer because, he said, "She looks the character – the sweet princess she is playing in Veer". After a screen test, Khan was given the lead role of Princess Yashodhara. 
Zareen Khan's second release was Sajid Khan's comedy film Housefull 2, a sequel of Housefull and Hindi remake of the Malayalam film Mattupetti Machan. 

In 2015, Khan appeared in erotic thriller film Hate Story 3, in which she played Siya. The film was a commercial success and got Khan further recognition. She then appeared in a music video "Pyaar Manga Hai" with Ali Fazal. The song was sung by Armaan Malik and Neeti Mohan. In 2016, Khan did an item number in the film Veerappan. The same year, she also appeared in another item song named "Mahi Ve" in the film Wajah Tum Ho.

In 2017, Khan appeared in Aksar 2. In the film, she was seen romancing with Gautam Rode, and the first poster of the movie was released on 4 August 2017 on YouTube. Umesh Punwani from Koimoi.com wrote ''Zareen Khan does good in parts but sadly she is majorly used for the skin show. Years into Bollywood she still can’t emote her expressions properly.'' Bollywood Hungama disliked Khan's performance and wrote ''Zareen Khan is strictly okay and though she is sizzling, it's done just for the heck of it. She tries to be the female Emraan Hashmi but it doesn't work for her. Performance-wise, she doesn't give her best shot.''

In 2018, Khan starred in Vikram Bhatt's horror film 1921, the fourth installment in 1920 film series. Shikta Sanyal of Koimoi.com called it ''Khan’s best performance till date.'' Although the film received mixed reviews, it managed to recover its cost and became an ''average grosser.''