Raised in Khetwadi, a Gujarati enclave of Bombay, Bhupen Khakhar was educated in the city and employed as a chartered accountant there beginning in 1958. His interest in art began as an avocation, and he enrolled in evening art courses at the JJ School of Art, Bombay in 1960. On the encouragement of his friend Gulammohamed Sheikh, an artist and art historian from Baroda, Khakhar entered the two-year art criticism course at the Faculty of Fine Arts, MS University, Baroda in 1962. Lived in Baroda for rest of his career. Khakhar's longstanding relationship with Gallery Chemould began in 1963.
Khakhar is known as India's first Pop artist, though relationship to Pop art more complex. His engagement with the bright colors usually confined to calendar art and middle-class homes and shops opened Indian art to an expanded range of colors. In the earliest stage of the artist's career, figures are designed and stylized in a manner akin to traditional and early modern Indian miniature painting. Aside from his lives as accountant and artist, Khakhar was also a well-known writer in Gujarati, crafting plays and stories inflected with the same humor and irony seen in his paintings.
After 1971, Khakhar began to paint deadpan imagery drawn from daily life in urban and small town India, focusing especially on workers engaged in middle-class professions. He drew not only on a modernist Pop style, but also from the late 18th-19th century Indian tradition of Company painting in his renderings of ordinary trade laborers - which included watch repairers, weathermen, and barbers. He was among six artists who participated in the landmark 1981 exhibition "Place for People." At that time also, Khakhar began to incorporate the experience of his own homosexuality into his artistic practice, which would be a central theme for the rest of his career.