A chance meeting with the writer, Wali Mohammad Wali, who worked for Dalsukh Pancholi, at a shop in Hira Mandi, Lahore, led to Pran winning his first role as a villain in Dalsukh Pancholi's Punjabi film Yamla Jat (1940), a big hit in that year. This followed by Chaudhary and Khajanchi. Soon he established a name for himself as a villain in the Lahore film industry, along with other noted villains of time, Ajit and K. N. Singh. Later, Pancholi also cast him in Khandaan (1942), which was the first Hindi movie in which Pran became a hero, opposite Noor Jehan, who had earlier acted with him as a child artist.
Pran had acted in 22 films as a villain before his career experienced a brief pause, due to the partition in 1947. He left Lahore, and arrived in Bombay on 14 August 1947, though films didn't come his way, in fact months of wait and unsuccessful hunting followed, after which he moved to smaller hotels and eventually ended up in Delmar Hotel, Marine Drive. It was only eight months later, in 1948, that he got a chance to start all over again, with the help of writer Saadat Hasan Manto and actor Shyam, he got a role in Bombay Talkies film, Ziddi (with Dev Anand and Kamini Kaushal as leads), directed by Shaheed Latif, launched his career in Bombay. This film was also Dev Anand's big break as a hero, and there was no turning for Pran from then on. Then within a week, he signed three more films, S M Yusuf's Grihasti, a diamond jubilee hit, Prabhat Films's Apradhi and finally Wali Mohammad, who had first lured him into movies in 1940, had by then also moved to Bombay, turned a producer and set up office at Famous Studios, near Mahalaxmi Racecourse, offered him Putli .
Pran was regularly offered the role of the main villain or negative character in the films with Dilip Kumar, Dev Anand and Raj Kapoor as the lead hero in the 50's and 60's. Pran's performance as the negative character was very much appreciated in Dilip Kumar starrers like Azaad, Madhumati, Devdas, Dil Diya Dard Liya, Ram Aur Shyam and Aadmi and films with Dev Anand as the lead man like Ziddi (1948), Munimji (1955), Amar Deep (1958) etc. and with Raj Kapoor in Aah,[disambiguation needed] Chori Chori, Jagte Raho, Chhalia, Jis Desh Men Ganga Behti Hai, Dil Hi Toh Hai. Subsequently in the sixties and early seventies, even though his age had catched up and he was in his forties, being slim and fit, his demand in the film market never went down and was given pivotal roles as a young character aged between 25-30 in films with Shammi Kapoor, Joy Mukherjee, Rajendra Kumar and Dharmendra as the lead hero. Whereas Dilip Kumar and Raj Kapoor's career as the young hero started to decline from the late sixties as both of them had put on lot of weight in the sixties although they were younger to Pran.But Pran's association with Dev Anand continued even beyond the 60's with super hits like Johny Mera Naam, Warrant[disambiguation needed] and Des Pardes. His film with him as the lead hero, Halaku[disambiguation needed] in 1956, was big hit too.
Pran always had a significant role in comedy films starring Kishore Kumar and Mehmood Ali in the lead roles. Pran's memorable collaborations with Kishore Kumar as the leading man include Naya Andaz, Aasha, Bewaqoof, Ek Raaz and Jaal Saz and with Mehmood in Sadhu Aur Shaitaan, Lakhon Me Ek. The most memorable films of Kishore Kumar and Pran together remains Half Ticket and Man-Mauji.