In December 1932, Griffiths joined the Benedictine monastery of Prinknash Abbey, where he was ordained to the priesthood in 1940. He spent some time in the sister abbey in Scotland but, after two decades of community life, moved to Kengeri in Bangalore, India in 1955 with the goal of building a monastery there. That project was unsuccessful.
In 1958, he helped Francis Acharya to establish Kristiya Sanyasa Samaj, Kurisumala Ashram (Mountain of the Cross), a Syriac rite monastery of Syro-Malankara Catholic Church in Kerala. In 1968 he moved to the Shantivanam (Forest of Peace) Ashram in Tamil Nadu, the ashram had been founded by the French Benedictine monk Abhishiktananda in 1950. Although he remained a Catholic monk he adopted the trappings of Hindu monastic life and entered into dialogue with Hinduism. Griffiths wrote twelve books on Hindu-Christian dialogue. Griffiths's form of Vedanta-inspired Christianity is called Wisdom Christianity.
Griffiths was a proponent of integral thought, which attempts to harmonize scientific and spiritual world views. In a 1983 interview he stated,
"We're now being challenged to create a theology which would use the findings of modern science and eastern mysticism which, as you know, coincide so much, and to evolve from that a new theology which would be much more adequate."
Griffiths died at Shantivanam in 1993, aged 86. The archives of the Bede Griffiths Trust are located at the Graduate Theological Union in Berkeley, California.