Wiley Hall is named in honor of Ephraim Emerson Wiley, the man who had the longest tenure of any president of Emory & Henry. A New England native and graduate of Wesleyan University, Wiley originally joined the College in 1838 as its first full-time faculty member. The building contains most of the College's administrative offices, a number of academic departments, and the college auditorium.

The current building was constructed in 1929, but it had two predecessors on the same site. The first was a fairly stark four-story structure known as "The College" because it served multiple functions as a residence hall for students and faculty as well as an instructional building. During the 74 years that "The College" remained standing, it was the scene of some of the most colorful events in the life of Emory & Henry, including a tragic shooting during the Civil War. The building had been taken over by the Confederacy for use as a hospital.

Eventually, the building was replaced by a more distinguished, strictly academic structure, very similar to the modern-day Wiley Hall. A fire in 1928 devastated all but the building's foundation, upon which the current Wiley Hall was constructed.