Upfold was born in Shenely Green, Surrey, England, and emigrated to the United States with his parents at the age of six.

[1] Two years later, Upfold abandoned his medical career took up theology.

[1] He was assigned to be deacon at Trinity Church in Lansingburg, New York in October 1818.

By 1855, the Diocese of Indiana had built is status and stability to the point that it could financially support the office of bishop, allowing Upfold to concentrate only on his duties as bishop.

They had two daughters, Sophia Bicker Upfold, who later married Joseph J. Bingham, editor of the Indiana Daily Sentinel;[3] and Emily L. Upfold, who became the librarian of the Diocese of Indiana.