As a young man, Sankey served in the American Civil War. He often helped the unit chaplain and led his fellow soldiers in hymn singing. After the war, he joined the Internal Revenue Service, and also worked with the Young Men’s Christian Association (YMCA). He became well known as a Gospel singer, and eventually came to the attention of evangelist Dwight Lyman Moody. The two men met at a YMCA convention in Indianapolis, Indiana, in June, 1870. Some months later, Sankey attended his first evangelistic meeting with Moody, and resigned from government service shortly thereafter.

In October 1871, Sankey and Moody were in the middle of a revival meeting when the Great Chicago Fire began. The two men barely escaped the conflagration with their lives. Sankey ended up watching the city burn from a rowboat far out on Lake Michigan.

Sankey composed about 1,200 songs in his lifetime. From 1895 to 1908, he was president of the Biglow and Main publishing company. He was blind from glaucoma the last five years of his life, and no doubt found a kindred spirit in his friend and music making partner, blind hymnist Fanny Crosby.