Mainstream work: 2003–present
In 2003, Bose entered mainstream Bollywood cinema with Jhankaar Beats in which he played one of two friends, R.D. Burman fans who are obsessed with winning a music competition. Boosted by a successful soundtrack, Jhankaar Beats was a surprise hit in urban multiplexes and went on to win several awards for its music. The same year, Bose appeared in another Bollywood film, Mumbai Matinee which saw a UK release. He starred in Chameli opposite Kareena Kapoor, playing a wealthy chain-smoking Mumbai banker who is stranded in the monsoon rains with a prostitute. The film was not a box office success, but won several Filmfare and IIFA awards.
He was the screenwriter of Hero Bhakti Hi Shakti Hai of Hungama TV in 2005.
Bose's second film pairing with Konkona Sen Sharma, 15 Park Avenue released in January 2006. Directed by Aparna Sen and filmed in English, 15 Park Avenue won the 2006 National Film Award for Best Feature Film in English.
With his next effort, the romantic comedy Pyaar Ke Side Effects, Bose moved once more into mainstream Bollywood cinema. The film follows the rocky relationship of Bose's commitment phobic Mumbai DJ Sid and his Punjabi girlfriend, Trisha played by Mallika Sherawat. Critics noted the freshness of Bose's narration style which involves breaking the fourth wall, a device not commonly used in Indian cinema. The film opened well in multiplexes and was a moderate financial success, eventually ranking among the top-grossing films of 2006. Both Bose and Sherawat received positive reviews for their performances. Sherawat and Bose also starred together in another Bollywood comedy, Maan Gaye Mughal-e-Azam (2008), which was a commercial and critical failure.
In 2006, Bose starred in the first of a trio of Bengali films, Aniruddha Roy Chowdhury's Anuranan. Anuranan was well received on the festival circuit and ran successfully for three months in Bengal. It was then dubbed into Hindi and released nationally. Kaalpurush, Bose's second Bengali film, was released commercially in April 2008. Kaalpurush details a father-son relationship and earned writer-director Buddhadeb Dasgupta a National Film Award for Best Feature Film. Bose teamed with Chowdhury again in 2009 for Antaheen which tells the story of online relationships. Like Anuranan, Antaheen was released commercially in West Bengal and was screened at various film festivals, including the Mahindra Indo-American Arts Council Film Festival (MIACC) and the International Film Festival of India (IFFI). Antaheen went on to win several National Awards including one for Best Film.
Bose continued working in a mix of mainstream and arthouse films in 2008, with the English-language film, Before the Rains. Before the Rains was released in the US and the UK and Bose's performance was praised by many critics, although the film received mixed reviews. Bose also appeared in Shaurya, a military court room drama modelled on the American film A Few Good Men. Bose's performance was well-received; critic Taran Adarsh said his "performance easily ranks as one of his finest works". His appearance in Dil Kabaddi paired him with Konkona Sen Sharma for the third time, this time playing a husband and wife undergoing marital difficulties. The Japanese Wife, with Japanese actress Chigusa Takaku, the third Aparna Sen film in which he has appeared, released on 9 April 2010. He also appeared as a contestant in the reality show Khatron Ke Khiladi where he was eliminated in the 12th round. He hosted the second series of Bloomberg UTV reality show The Pitch. His role as a gay man harassed by the police in I Am was appreciated by critics.
He appeared in Deepa Mehta's version of Midnight's Children where he played the role of General Zulfikar. He also played the villain in the 2013 Tamil film Vishwaroopam. Naren Weiss who was 19 years old at the time, acted opposite Bose in all of his scenes for Vishwaroopam, and credited Bose for working with him during filming. He was scheduled to begin shooting his adaptation of Mohsin Hamid's novel, Moth Smoke in early 2010, but the project was postponed after the film's financial backers pulled out. In 2013, he also played opposite Konkona Sen Sharma again in Suman Mukhopadhyay's Shesher Kabita. In 2017, he directed, produced and acted in the biopic Poorna about the youngest girl to climb Mount Everest.