It is sited adjacent to The Carnegie Mellon Software Engineering Institute (SEI) and the University of Pittsburgh's Bellefield Hall and is across Bellefield Avenue from two other local landmarks: the University of Pittsburgh's Heinz Memorial Chapel and the Cathedral of Learning.

Designed by architect Benno Janssen (1874–1964), the Mellon Institute building has neo-classical architecture and elegant construction, with its signature monolithic limestone columns (the largest monolithic columns in the world).

[citation needed] The two extra pillars were buried in the large lawn beside the Cathedral of Learning.

In 2013, the American Chemical Society recognized the Mellon Institute as a National Historic Chemical Landmark for its contributions to industrial research and training from its inception in 1913 until its merger with the Carnegie Institute of Technology.

[5] For decades, the columns of the Mellon Institute building have served as a popular background for photographers shooting Pittsburgh wedding parties.