Upon first meeting with his spiritual master, Srila Bhaktisiddhanta Sarsvati Thakura, in 1922 it was requested that Prahhupada spread Vedic knowledge throughout the English language. In 1933 he became a formally initiated disciple. Starting in 1944 and without assistance he started Back to the Godhead, an English language fortnightly for which he acted as publisher, editor and copy editor. In 1947 the Gaudiya Vaisnava Society recognised Prabhupada's scholarship with the honourific Bhaktivedanta (Sanskrit: Devoted Lover of Vedanta. See Bhakti and Vedanta). Beginning in 1950 he lived at the medieval Temple of Radha-Damodara in the holy city of Vrndavana. He took sanyasa vows in 1959 following which he published his 30 volume translation of the 18,000 verse Srimad-Bhagavatam and the commentary on it. He then left India to fulfill his master's spiritual mission. Arriving virtually penniless by freighter in New York, he was first helped by the Hippies who were openly searching for "Truth". His first converts were from among them.

In the 12 years from his arrival in New York until his death he:

• circled the globe 14 times on lecture tours that took him to 6 continents.
• introduced Vedic gurukul education to a Western audience.
• directed the founding of The Bhaktivedanta Book Trust, the world's largest publisher in the field of Indian religious texts and commentary.
• founded New Vrindaban
• authored 60 books on Vedantic philosophy, religion, literature and culture (including 4 in Bengali)
• watched ISKCON grow to a confederation of more than 100 schools, temples, institutes, farm communites and ashrams.