The campus includes eighteen buildings and access to the 200-acre (80.9 ha) Thoreau Wildlife Sanctuary.

[3] The college began as Defiance Female Seminary in 1850 and was opened by the Christian Connection, which itself later became part of the United Church of Christ, to provide schooling for young women.

During President Kevin McCann's leadership (1951–1964), the campus increased in size to 140 acres (56.7 ha); the library, student union, and Pilgrim halls were built; and old buildings were renovated.

On October 15, 1953, he laid the cornerstone for the Anthony Wayne Library of American Study [1].

The Defiance College Yellow Jackets compete in Wolverine-Hoosier Athletic Conference (WHAC) in every sport except for football, where they are a member of the Mid-States Football Association (MSFA) and are a part of the National Association of Intercollegiate Athletics (NAIA).