His father, Kikubhai Desai, was an Indian film producer and owner of Paramount Studios (later Filmalaya) from 1931 to 1941. His productions, mainly stunt films, included Circus Queen, Golden Gang, and Sheikh Challi. Manmohan Desai's older brother, Subhash Desai, became a producer in the 1950s and gave Manmohan his first break with the Hindi film Chhalia (1960). Subhash later went on to produce Bluff Master, Dharam Veer, and Desh Premee with Manmohan as the director.
Manmohan Desai was known for his family-centered, action-song-and-dance films which catered to the tastes of the Indian masses and through which he achieved great success. His movies defined a new genre called masala films. His best known super-hit movies were Amar Akbar Anthony and Dharam Veer.
He had a string of hits with Amitabh Bachchan in the 70s and early 80s which helped cement Bachchan's status as a superstar of Indian cinema. He worked with Amitabh on Amar Akbar Anthony, Parvarish, Suhaag, Naseeb, Desh Premee, Coolie, Mard and Ganga Jamuna Saraswati; all but the last were box office successes. He was one of the directors who had a special working relationship with Amitabh Bachchan, the others being Yash Chopra, Prakash Mehra, Ramesh Sippy, and Hrishikesh Mukherjee. Of these, only Yash Chopra went on to make hits beyond the 1980s.
He often worked with the same actors in several different films:
- Jeetender in Dharam Veer (1977) after Bhai Ho To Aisa
- Shatrughan Sinha in Naseeb after Bahi Ho To Aisa and Aa Gale Lag Jaa (1973) and Rampur Ka Lakshman (1972)
- Shashi Kapoor in Suhaag after Aa Gale Lag Jaa (1973)
- Shammi Kapoor in Parvarish (1977) as a father figure after Junglee and Bluffmaster (1963)
- Randhir Kapoor in Chacha Bhatija (1977) after Rampur Ka Lakshman (1972).
Apart from Bachchan, Manmohan Desai worked with such leading male stars as Raj Kapoor in the 1960 film Chhalia, Shammi Kapoor in "Bluffmaster" (1963), Rajesh Khanna in Sachaa Jhutha (1970) and Roti (1974), Randhir Kapoor in Raampur Ka Lakshman (1972), Shashi Kapoor in "Aa Gale Lag Jaa" (1973), Dharmendra in Dharam Veer (1977). 1977 was an exceptional year for him. All four of his films released that year were huge hits: Parvarish, Amar Akbar Anthony, Chacha Bhatija and Dharam Veer. The first two were with Amitabh, and the latter two were with Dharmendra.
Manmohan Desai worked with writers such as Prayag Raaj, K.K.Shukla and Kader Khan and lyricists such as Anand Bakshi, Sahir Ludhianvi, Qamar Jalalabadi, Gulshan Bawra, and Shailendra. Early in his career he worked with composers Rahul Dev Burman, Kalyanji Anandji, later with Laxmikant Pyarelal and in the 1980s with music composer Anu Malik.
Out of the 20 films that Desai directed in his career span of 29 years (1960–1989), as many as 13 films were stupendous hits. His success ratio was 65 percent in an industry where flops abound. His favourite playback singer was Mohd Rafi. In most of his movie, Mohd Rafi was used to sing songs beside Kishore Kumar. When Kishore Kumar voice was frequently used on Amitabh Bachcan by other Directors, he used Mohd Rafi's voice on Amitabh Bachcan in films like Suhaag and Parvarish. His biggest hits of Mohd Rafi is like song Pardah Hai Pardah from Amar Akbar Anthony and John Jani Janardhan from Naseeb. Manmohan Desai once said that Mohd Rafi voice is God's voice.
Towards the end of his career, Desai's previously successful stories and style began to lose favour with audiences. Critics accused him of self-parody. His last film as a director Ganga Jamuna Saraswati and the films he produced with his son Ketan Desai directing, Allah Rakha and Toofan, failed at the box office.
Manmohan Desai was of Gujarati ancestry. His wife was Jeevanprabha Desai. She died in April 1979. He was engaged to actress Nanda from 1992 until the time of his death in 1994. He had one son Ketan Desai who is still involved in the film industry. Ketan is married to Kanchan Kapoor, daughter of Shammi Kapoor and Geeta Bali.
On 1 March 1994, per news Manmohan Desai fell from the balcony in Khetwadi as the rail he was leaning on collapsed and died. Very little is known about his death except that he was suffering from chronic back pain. Rumours of him committing suicide have not been confirmed.