Ezekiel's first book, The Bad Day, appeared in 1952. He published another volume of poems, The deadly man in 1960. After working as an advertising copywriter and general manager of a picture frame company (1954–59), he co-founded the literary monthly Jumpo, in 1961. He became art critic of The Times of India (1964–66) and edited Poetry India (1966–67). From 1961 to 1972, he headed the English department of Mithibai College, Bombay. The Exact Name, his fifth book of poetry was published in 1965. During this period he held short-term tenure as visiting professor at University of Leeds (1964) and University of Pondicherry (1967). In 1969, Writers Workshop, Ezekiel published his The Damn Plays. A year later, he presented an art series of ten programmes for Indian television. In 1976, he translated Jawaharlal Nehru poetry from English to Marathi, in collaboration with Vrinda Nabar, and co-edited a fiction and poetry anthology. His poem The Night of the Scorpion is used as study material in Indian and Colombian schools. Ezekiel also penned poems in ‘Indian English’  like the one based on instruction boards in his favourite Irani café. His poems are used in NCERT and ICSE English textbooks.
Nissim Ezekiel is often considered the father of Modern Indian English poetry by many critics.
He was honoured with the Padmashri award by the President of India in 1988 and the Sahitya akademi cultural award in 1983.