Founded in 1844, and renamed Knox College in 1846, this Presbyterian theological institute retained architects Smith and Gemmell in 1873 to design a Gothic Revival structure in the centre of Spadina Crescent. Completed two years later, the distinguished High Victorian edifice became the home for the College for the next 31 years. The building boasted a convocation hall, classrooms, a library, and dormitories for almost 100 divinity students. With its landmark location, bermed landscape, and southern orientation the former college building attracts attention away from its more modern surroundings. Knox College must have thoroughly dominated the 19th century urban setting in the days of horse and buggy.

The building is composed of an axially symmetrical centre block and square tower, with supporting gabled wings to the east and west. Among the medieval-inspired elements are the pointed windows, angled buttresses on the walls, rounded buttresses on the towers, engaged columns, finials, gargoyles, corbel tables, and steeply pitched dormers. The buff brick walls are divided by a series of horizontal drip courses and window hoods of sandstone. The windows, grouped in larger brick arches, diminish in size from the ground to third storey, increasing the sense of height. The circular motifs centred on the upper third of the lancet window mullions add interest and bring unity to the fenestration. Much of the interior has been altered, but the groin-vaulted main vestibule at the south, arched halls on the ground floor, and central oak staircase remain as faint echoes of the Gothic exterior. The overall architecture is restrained, conservative, and markedly institutional.

The College building later became the Spadina Military Hospital, then, after being repurchased by the University of Toronto in 1943, the Connaught Laboratories – famous for its historical association with the development and production of penicillin and insulin. In subsequent years there have been several additions to the rear of the main block, most of which have been less than sympathetic to the original design. Today the building is occupied by various university departments, medical laboratories, and other campus organizations.

Sean C. Fraser