St. Mary's School was an American parochial girls' school located in Knoxville, Illinois. It opened in April 1868, in the building of the Ewing Female University, erected about ten years before. For lack of endowment, that institution had been compelled to discontinue its work, and the property was transferred to the Episcopal diocese of Illinois. Of the fifteen trustees, ten were appointed to represent the diocese of Illinois and five to represent Knox county. The Rev. Charles Wesley Leffingwell became the founder and rector of St. Mary's, Mrs. Leffingwell being the matron and Miss Nancy Menedy Hitchcock the vice-principal. Dr. Leffingwell continued for 52 years as rector of the school; Mrs. Leffingwell was matron for 40 years; Miss Hitchcock was vice-principal for over 25 years. This institution was entirely rebuilt and refurnished in 1883, at a cost of over US$100,000. Chapel, cloister, and other improvements were added.

Knoxville is a city in Knox County, Illinois, United States. The population was 2,911 at the 2010 census. It is part of the Galesburg Micropolitan Statistical Area.