Khan made his screen debut in 2003 in the film Chura Liyaa Hai Tumne.[4]
In 2004, he starred in Main Hoon Na, which was one of the biggest hits in his career. It was the second highest-grossing film of 2004 behind Veer-Zaara and was declared a hit. Khan was subsequently nominated for the Filmfare Award for Best Supporting Actor in 2005. He also starred alongside Amrita Arora in a music video called Disco 82 Remix by DJ Aqeel for UMI-10.
Khan had 4 releases in 2005. He played an obsessive lover in Vaada alongside Arjun Rampal and Ameesha Patel. He then starred in Shabd as a photography professor, which he was very excited about because he had always wanted to do a film with Aishwarya Rai. His third release, Anubhav Sinha's action thriller Dus, where he played a cop, did well. It was an above-average grosser and was the third highest-grossing film of 2005. Khan's final release of the year, Shaadi No. 1, flopped at the box office.
He starred in Sohail Khan's action multi-starrer, Fight Club - Members Only in 2006. Next, he appeared in Rocky: The Rebel. Khan revealed that he had ghost-written some scenes in the film. He had first begun script-writing when he was studying in London.
Both of his films in 2007 were action multi-starrers. Anubhav Sinha's Cash was originally meant to be the sequel to Dus, but ended up differently. Due to this, some of the cast of Dus also star in Cash. It performed reasonably well in its first week, but was unable to replicate the success of Dus and was eventually declared a flop. Speed also failed.
In 2008, Khan had the leading role as a news reporter in Apoorva Lakhia's Mission Istaanbul opposite Vivek Oberoi. He also starred in the Bollywood remake of Rain Man, Yuvvraaj with Salman Khan, Katrina Kaif and Anil Kapoor.
The following year, he featured in the underwater action thriller Blue. At the time of its release, the film broke the record for having the highest budget for a Bollywood film. It had an excellent opening weekend on Diwali, collecting ₹480 million, but was a below-average grosser. He also filmed Sharafat Gayi Tel Lene", a comic thriller film. However, it ran into production hassles and is yet to be released.
Khan had a special appearance as an infidel fiancé in the Ranbir Kapoor–Priyanka Chopra starrer, Anjaana Anjaani.
In 2011, the actor ventured into production with his co-owned production house, Born Free Entertainment along with good friend Dia Mirza and her fiancé Sahil Sanga. Their first film, Love Breakups Zindagi, was released on 7 October 2011, and was met with a lukewarm response.
In 2012, Khan played a supporting role in Tezz, which stars Anil Kapoor and Ajay Devgan in the lead. His next film, Ameesha Patel's maiden production, Desi Magic, is slated to release on 28 February 2015.
In August 2017, it was announced that Bollywood actor Zayed Khan will soon be making his television debut on a show called Haasil playing the lead role of Ranvir Raichand opposite Vatsal Sheth and Nikita Dutta.[5] The show will premiere in October 2017.