Her relationship with filmmaker Vikram Bhatt was often talked about in the Indian media as well as her long-running rift with her parents.
Debut and breakthrough, 2000–2002
Patel's first opportunity for acting came in the form of an offer from her father's schoolmate, Rakesh Roshan, to star opposite his son, Hrithik Roshan, in Kaho Naa... Pyaar Hai (2000). The offer came immediately after she graduated from high school but she refused the project because she wanted to continue her education in USA. Afterward, Kareena Kapoor replaced her but luckily, Kapoor backed out after shooting for a couple of days and Patel was given the opportunity once again during a family lunch. Patel readily agreed to do the project this time. The role of an exuberant college girl in love, undergoing a tortuous time at losing her lover and rediscovering a more mature relationship gave Patel scope to perform. The film was a smashing success and established Patel as a rising star, earning her awards for Best Debut at a number of award ceremonies.Patel as the Muslim girl Sakeena in Gadar: Ek Prem Katha (2001).
In her second film, the Telugu language drama Badri, she starred opposite Pawan Kalyan. The film was a major success, grossing more than Rs 120 million in India.
2001 saw her appearing in Anil Sharma's cross-border romance, Gadar: Ek Prem Katha, alongside Sunny Deol. Patel signed on much before she shot into the limelight with Kaho Naa... Pyaar Hai and was among 22 girls that were screen-tested from 500 girls who came to audition for the film. Patel had gone through a 12-hour audition before she got the part. 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. Set during the Indo-Pakistani War of 1947, it featured Patel as Sakeena, 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, as well as nominations for Best Actress at various award ceremonies. Taran Adarsh of IndiaFM concluded, "Despite being one-film-old, Amisha Patel deserves full marks for handling the complex role with elegance. She looks the character she is portraying and impresses with a natural performance."The film was perceived as being excessively anti-Pakistani.
These successes were followed by a series of films that flopped at the box-office. In Yeh Zindagi Ka Safar (2001), she played a successful singer who was abandoned by her mother at the time of her birth.
In 2002, Patel had four continuous failures but her last release, Humraaz, became one of the highest grossing films of the year at the box office, and her performance earned her a nomination for Filmfare Best Actress Award. The Abbas-Mustan marital thriller saw her playing a character with negative shades for the first time. She played the girlfriend of Akshaye Khanna, who marries Bobby Deol to grab his wealth – but, seeing Bobby's honesty, her character surrenders to him. Taran Adarsh commented, "Amisha Patel is just about okay as Akshaye's lover (first half), but splendid as Bobby's wife (second half). This performance should silence her detractors for sure. Also, she's looked her best with admirable outfits and perfect make-up."
 Career slump, 2003–2006
During 2003 to 2006, Patel's acting career entered a slump. Despite the relative success of Humraaz, Patel's string of unsuccessful films followed and would continue until 2006, although she did find minor box office success with Kya Yehi Pyaar Hai, in which she played a career-oriented young woman who rejects the advances of the film's hero. In Aap Mujhe Achche Lagne Lage, she played the role of Sapna who is caged in protective custody of her own father. She co-starred opposite Hrithik Roshan for the second time in this film. Unlike their successful pairing in Kaho Naa... Pyaar Hai, the film proved to be a disappointment and resulted in a critical and commercial failure. Patel's performance in the film was criticized by a section of the media, but during an interview she clarified that there was an "error" because the scene explaining that her character is supposed to be asthmatic in the film was edited out not knowing that one shot would make such a difference, thus creating confusion to the viewer about her appearing out of breath, as if she's overacting or crying.
Consequently, Patel's unsuccessful follow-up continued with Kranti and David Dhawan's comedy Yeh Hai Jalwa in 2002, followed by her first Tamil language film Puthiya Geethai and Deepak Bahry's Parwana in 2003. Her releases in 2004, Vimal Kumar's comedy Suno Sasurjee, a delayed production since 2000, and her second Telugu language film Naani, followed. That year she also appeared in the music video for "Kasam" and "Kasam (Unplugged)" by Adnan Sami.
In 2005, she starred in Satish Kaushik's thriller Vaada, playing the role of Arjun Rampal's unfaithful wife who is followed by her obsessive ex-lover. In her next release, Elaan, she played a TV reporter. She later appeared in Ketan Mehta's historical drama Mangal Pandey: The Rising where she played the role of the soft-spoken Jwala, a Bengali widow who gets rescued from committing Sati by a British commanding officer. Patel was cast as a replacement for Aishwarya Rai under the recommendation of Aamir Khan who was impressed by her IQ level when he saw her on BBC under the segment of Question Time India in 2003. The film, which saw her appearing without make-up for the first time, did an average business despite becoming a major grosser. Her other releases that year include Zameer: The Fire Within, a delayed production since 2001, and the Telugu film Narasimhudu, both which proved commercial and critical failures.
Patel featured in six films in 2006, all which failed commercially. She first starred in Mere Jeevan Saathi, a production that had been delayed since 2003. She next appeared as a blind girl in Humko Tumse Pyaar Hai, another delayed production since 2002. The film had a very small release and flopped badly with some critics describing it as "outdated". In Teesri Aankh: The Hidden Camera, she played the role of a mute girl who witnesses a murder. She learned the sign language in order to fit the role. Patel was next cast in Tathastu, based on Denzel Washington's thriller John Q (2002). Her performance as the helpless mother was not well-received.
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