Patel made her acting debut with Rakesh Roshan's Kaho Naa... Pyaar Hai. The film was the biggest hit of the year, and made her a star overnight, earning her awards for Best Debut at a number of award ceremonies.[4] She next appeared in the cross-border romance, Gadar: Ek Prem Katha, alongside Sunny Deol. The film went on to become the top grossing film of the year, as well as the biggest hit of the 21st century, earning RS 973 million In India.[5] Set during the 1947 Indo-Pakistani conflicts, it featured Patel as Sakina, a Muslim girl who finds refuge in Deol's house during the riots, and subsequently falls for him. Her performance was praised, and won her the Filmfare Special Performance Award.

These successes were followed by a series of films that flopped at the box-office. In Yeh Zindagi Ka Safar (2002), she played the role of a successful singer who was abandoned by her mother at the time of her birth. In Kya Yehi Pyaar Hai (2002), she plays a career-oriented girl who rejects the advances of the hero. In Humraaz (2002) she played the selfish girlfriend of Akshaye Khanna, who marries Bobby Deol to grab his wealth -- but, seeing Bobby's honesty, her character surrendered to him. In 2005 she starred opposite Hollywood actor Tobey Stephens in the historical epic film Mangal Pandey: The Rising where she played the role of a widow who gets rescued from committing Sati by a British man.

After many flop films in 2006, Amisha finally had another hit in October 2007 with the hit movie Bhool Bhulaiyaa where she played the role of a rejected adopted girl.

Amisha's next release is Yash Raj Films' Thoda Pyaar Thoda Magic in which she's co-starring Rani Mukerji and Saif Ali Khan. Both Amisha and Rani are playing pivotal roles opposite Saif Ali Khan.

She has also signed onto two big projects, one opposite Govinda titled Do Lucky, and another opposite Bollywood superstar Sanjay Dutt titled Chatur Singh Two Star. Both are comedies.