Born in Shelbyville,Tennessee, William E. Guy attended Illinois College in Jacksonville, Illinois, and was its first Black graduate in 1899. Additional coursework is unknown, but by the 1920s he was sometimes referred to as Dr. William Guy.

He pastored at St. Paul AME Church in Des Moines, Iowa from 1930 through late 1932, having previously served in Oklahoma, Kansas, Michigan, and Windsor, Ontario. His portrait is included in a small feature in the Des Moines Tribune on October 11, 1930. Guy would later minister in Fort Wayne and Indianapolis, Indiana and St. Paul, Minnesota. He was presiding elder for the St. Paul District of the AME Church and visited Iowa in the 1940s. He died in Kansas City, Missouri with funeral services in Springfield, Illinois. He has a gravestone in Oak Ridge Cemetery, Springfield, Illinois. Illinois College has a small archive connected to his life and featured him in a display in 2025.