Preity Zinta's first role in 2000 was in the drama Kya Kehna, which unexpectedly became a box office success. The film addressed themes of single parenthood and teenage pregnancy, and gained Zinta wider recognition from the public as well as film critics. Her portrayal of Priya Bakshi, a teenage single mother who fights social prejudice, earned her several award nominations, including her first nomination for Best Actress at the Filmfare Awards. Anupama Chopra from India Today reported that Zinta belonged to a new breed of Hindi film actors that breaks away from character stereotypes.

Later that year, Zinta starred in Vidhu Vinod Chopra's drama Mission Kashmir alongside Sanjay Dutt and Hrithik Roshan. Set in the valley of Kashmir during the Indo-Pakistani conflicts, the film dealt with the topic of terrorism and crime. Zinta's role was that of Sufiya Parvez, a TV reporter and Roshan's childhood love. A review in The Hindu said about her performance, "Preity Zinta is her usual cherubic self and lends colour to the otherwise serious proceedings". It was an economic success, becoming the third-highest-grossing film of the year in India.

Zinta was the female lead in India's three highest-grossing films of 2003: The Hero: Love Story of a Spy, Koi... Mil Gaya and Kal Ho Naa Ho.
n 2004 she starred as TV journalist Romila Dutta in Farhan Akhtar's war drama Lakshya, alongside Hrithik Roshan. The film was based on the historical events of the 1999 Kargil War; Zinta's character was modelled after TV journalist Barkha Dutt, the only female reporter who covered the conflict.

In 2005, Zinta appeared in two films. Her first release was the folk comedy Khullam Khulla Pyaar Karen, co-starring Govinda, a production that had been delayed since 2002.

Zinta received further success in 2006, starring in Karan Johar's romance drama Kabhi Alvida Naa Kehna with an ensemble cast including Amitabh Bachchan, Shahrukh Khan, Abhishek Bachchan, Rani Mukerji and Kirron Kher.

In 2011, Zinta made her television debut as the host of the show Guinness World Records – Ab India Todega on Colors Channel. An Indian version of Guinness Book of World Records, the show premiered on 18 March to an audience measurement of 3.3 rating points, which made it occupy the 7th position on the chart of celebrity-driven reality shows on Hindi entertainment channels. In a four-star review for Hindustan Times, critic Rachana Dubey wrote, "Preity is a riot. She's vivacious and knows exactly when she needs to be serious and when she can crack jokes." Later that year, Zinta started hosting the celebrity-based chat show Up Close & Personal with PZ, shot at her own penthouse in Mumbai and broadcast on the newly launched channel UTV Stars. The first episode aired on 3 September. In 2015, Zinta featured as a talent judge for the seventh season of the dance reality show Nach Baliye