He started in the late 1950s as a production controller. In 1968 he directed Shashi Kapoor who played a double role in Haseena Maan Jayegi. This was followed by the 1971 hit Mela starring the Khan brothers (Feroz Khan and Sanjay Khan) together. In 1973 he produced and directed Zanjeer. The role was offered to a a relative newcomer Amitabh Bachchan as established stars were not available. The role was of a serious police officer who wants revenge, and a break from the then popular musical romances. The movie was a huge hit and established Amitabh as a solo actor ( his previous roles of note having been in support roles). It established Amitabh's early peronnna (an angry young man fighting the system on his own terms) and started an association that spawned 6 more movies - Hera Pheri, Muqaddar Ka Sikandar (1977), Laawaris (1981), Namak Halaal (1982), Sharaabi (1984) and Jaadugar (1989) All except Jaadugar being hits. In 1974 he also had a hit as a director with his other favourite star- Vinod Khanna, with the movie Haath Ki Safai.
Prakash Mehra also directed & produced Zindagi Ek Juaa with actor Anil Kapoor in 1991 which was not a commercial success. In 1996 he introduced veteran actor Raaj Kumar's son Puru Raj Kumar in Bal Brahmachari which was also unsuccessful. Mehra received a lifetime achievement award from the India Motion Picture Producer & Directors Association in 2006.
Prakash Mehra was one of the first Bombay directors to try venture into Hollywood. In the late eighties he tried a joint venture to make the movie The God Connection' with Frank Yandolino. The movie was to include Hollywood actors such as Charles Bronson among others, but the project though funded heavily initially, never materialized.
Prakash Mehra along with Manmohan Desai, Hrishikesh Mukherjee and Yash Chopra have accounted for a large number of Amitabh's famous hits. Of these only Yash Chopra went on to make hits beyond the 1980s.