Born and raised in Scotland, Main performed brilliantly at school and studied business at Glasgow, where he had a conversion experience in 1873, and joined the evangelistic revival movement, meeting D. L. Moody and Ira Sankey in 1874. An encounter with a medical missionary inspired him to become a medical missionary himself. Educated at Edinburgh with the help of the Edinburgh Medical Missionary Society, he sailed with his wife, Florence Nightingale (Smith), for China in 1881 under the Church Missionary Society. They 1ived at Hangchow (Hangzhou) for their entire service, in spite of frequent revolutionary unrest. When the Mains left China in 1926, at least thirty different medical and welfare institutions had been established through their efforts.