It was founded in 1912 by Mary Kimball Morgan with the purpose of "serve the Cause of Christian Science." According to the college, it has no affiliation with the Church of Christ, Scientist, but "the practice of Christian Science is the cornerstone of campus life." Students and staff are practicing Christian Scientists.

Principia sits on bluffs overlooking the Mississippi River between Alton and Grafton in the Metro East region of Southern Illinois, thirty miles north of St. Louis. A portion of the schools 2,500-acre (1,000 ha) campus is a designated National Historic Landmark District, for its many buildings and design by architect Bernard Maybeck.