Upjohn was born on March 7, 1828, in Shaftesbury, Dorsetshire, England and his family emigrated to the United States in 1829.

The earliest building that architectural scholars credit to him alone is Madison Square Presbyterian Church in New York City, built from 1853 to 1854.

[3] A number of noteworthy architects trained in his office, including Clarence Fagan True.

[4] A number of buildings that he designed are now listed on the National Register of Historic Places (NRHP).

[6] Together, they were the parents of three daughters and five sons, including Hobart Upjohn, who practiced as a civil engineer and architect.