Nagesh was born as Gundu Rao to Krishna Rao and Rukmaniamma in 1933. He was born in Dharapuram, now in Tiruppur district, Tamil Nadu. He left Dharapuram at an early age and moved to Madras city in search of a career. His roommates, the writer Vaali and director Sridhar, later became established themselves as prominent personalities in the Tamil cinema field. He worked as a clerk in the Indian Railways. He was educated in Madras and worked as a clerk in the Indian Railways before carving a place for himself in the Tamil film industry. He acted in over 1,000 Indian movies from 1958 to 2008 performing in a variety of roles as comedian, hero, supporting actor and villain. He died on January 31, 2009. Despite being primarily a comedian, Nagesh was rated highly as a character actor by his peers. Nagesh's style of comedy was largely inspired by Hollywood icon Jerry Lewis. Similarities between Nagesh and Jerry Lewis earned Nagesh the sobriquet "Jerry Lewis of India".
He was a heavy smoker and drinker and later gave them up due to his ill health. He married Regina and has two sons Ramesh Babu and Anand Babu. He initially played small roles in dramas. He was given a chance in the film Manamulla Marudhaaram in 1958. However this was a failure. His debut movie in Kannada was Makkala Rajya in 1960. He was praised for his performance in the film Thayilla Pillai. He came to limelight after his role in the film Nenjil Oru Aalayam in 1962. The film Server Sundaram which is said to depict his own life history gave him a major break in the film industry. Nagesh's career witnessed a decline from the mid-1970s onwards. He was plagued by personal problems. His marriage to a Christian woman named Regina had fractured his relationship with his mother and other relatives. From the relationship, he had three sons, Anand Babu, Ramesh Babu and Rajesh Babu, the first son going on to be an actor plagued by personal problems in his career. In 1973, his mother died causing him irreparable grief. At about the same time, he had a fallout with Tamil actor and politician MGR, whose fellow producers omitted Nagesh from most of his films. The Nagesh theatre he owned in Chennai was on the verge of being seized for non-payment of dues forcing Nagesh to patch up differences with MGR who subsequently bailed him out. But later in the 1970s and 1980s, when MGR was the chief minister, Nagesh and MGR resumed the age old friendship on stages and screens. To cope with the changing trends, Nagesh had to switch over to playing character roles full-time.
His career enjoyed a partial resurgence from the 1980s onwards when he acted in a number of movies, mostly in elderly roles, some of them as the villain. His most remembered role as a villain was in the 1989 hit Apoorva Sagodharargal. The movie was later dubbed into Hindi as Appu Raja. He also played the villain in Rajinikanth films Athisaya Piravi and Mounam Sammadham. His negative roles included sadistic schemers, then muscular giants.