Deol made his film debut in the 2005 Imtiaz Ali's Socha Na Tha, a romantic comedy where he starred opposite Ayesha Takia. The film garnered mostly positive reviews from critics and was an average grosser at the box-office. Deol's performance in the film was well received. His second film role was 2006's Ahista Ahista. Deol's first 2007 release was the multi-starrer comedy drama Honeymoon Travels Pvt. Ltd. which emerged as a box-office success. Deol had two more releases in the year, the crime film Ek Chalis Ki Last Local and the thriller Manorama Six Feet Under. The latter won the Best Film at the Mahindra Indo-American Arts Council Film Festival in New York City, and Deol won the Best Actor Award.

After the modest success of his debut, Deol garnered praise for his performances in films including Manorama Six Feet Under (2007), which won him the Best Actor Award at the Indo-American Arts Council Film Festival, and the commercially successful Oye Lucky! Lucky Oye! (2008). His breakthrough role came in 2009 with the starring role as Dev in Anurag Kashyap's critically and commercially successful Dev.D, a modern-day adaptation of the Bengali classic novel Devdas. With the success of the film, Deol gained wider recognition and further praise from film critics.

Deol's sole release of 2008 was black comedy film Oye Lucky! Lucky Oye!. Directed by Dibakar Banerjee, the film had Deol portray a compulsive thief, Devinder Singh a.k.a. Bunty, and the film's plot follows his exploits. Oye Lucky! Lucky Oye! was met with critical acclaim, but suffered heavily because of the timing of its release, a day after the 2008 Mumbai attacks, leading to widespread fear of crowded places.

Deol has been described by the Indian media as an actor who continuously understands how to play complex characters. He has appeared on the several magazine covers including the Man's World and the Time Out Mumbai, with titles such as "The New Face of Indian Cinema". In 2009, Deol was included in the list of Zoom's "50 Most Desirable Hotties", being placed seventh. Deol learned the Israeli martial art Krav Maga.

In 2011, Deol starred in Zoya Akhtar's comedy drama road movie Zindagi Na Milegi Dobara alongside Hrithik Roshan, Farhan Akhtar, Katrina Kaif and Kalki Koechlin. The story that follows three friends, who have been inseparable since childhood, had him play the role of Kabir, an Architect. They set off to Spain on a bachelor trip for Kabir who is set to be married to Natasha, an interior designer played by Koechlin. He trained to be a deep-sea diver for the film which was filmed in Spain. The film opened to critical acclaim and grossed ₹1.53 billion (US$23 million) worldwide, surpassing Dhoom 2 in the worldwide gross, becoming the ninth highest worldwide grosser of all time for a Bollywood film, at the time of its release.

Deol had two releases in 2012, both of which were political thrillers– Dibakar Banerjee's Shanghai and Prakash Jha's Chakravyuh. In the latter, Deol starred alongside Arjun Rampal as a police informer, but later gets involved in a Naxalite movement. The film received mixed reviews from film critics. Shanghai co-starring Emraan Hashmi and Kalki Koechlin was based on the French novel Z by Vassilis Vassilikos. The film opened to positive reviews and Deol's performance as a bureaucrat/IAS officer garnered much acclaim. Raja Sen of Rediff.com applauded Deol writing that he, " wears his inscrutability thickly and delivers a strong performance". The film was a surprise hit and went on to gross over ₹200 million (US$3.1 million) in India.