In 1857, Keshab Sen took up a clerkship, this time as a private secretary to Dwijendranath Tagore and joined the Brahmo Samaj. In 1859, Sen dedicated himself to the Acharya, organisational work of the Brahmo Samaj, and in 1862 was assigned, by Hemendranath Tagore, a stipendiary ministry (Acharya) of one of its Worship Houses despite being a non-Brahmin (previously a Shudra, untouchable, had been made an Acharya by Debendranath Tagore).
In 1858, he left his home in Colootola and took refuge in the Jorasanko House of the Tagore family when the patriarch of the family was then away. In 1862, Sen helped in the founding of Albert College and wrote articles for the Indian Mirror, a weekly journal of the Calcutta Brahmo Samaj in which social and moral subjects were debated.
In 1863, he wrote the Brahmo Samaj Vindicated. He strongly criticised Christianity and travelled about the country lecturing and preaching that the Brahmo Samaj was intended to revitalize Hindu religion through use of ancient Hindu sources and the authority of the Vedas. By 1865, however, Sen was convinced that only Christian doctrine could bring new life to Hindu Society.
In 1865, he left the Brahmo Samaj after "an open break with its founder Debendranath Tagore" over Christian practices in Brahmoism, and the next year (1866) with encouragement of the Unitarian Preacher, Charles Dall, he joined another new organisation Bharatbarshiya Brahmo Samaj as its secretary (president being god). Tagore's Brahmo Samaj then quickly purged itself of Sen's Christian teaching and encouraged being described as Adi Brahmo Samaj to distinguish it from Sen's deliberately eponymous version.
