The diocese was created by Pope Leo XIII on January 23, 1890.

It has also previously operated under the name the Roman Catholic Diocese of Alexandria in Ontario.

The see of Alexandria-Cornwall was vacant following the appointment of then-bishop Marcel Damphousse as the Bishop of Sault Sainte Marie on November 12, 2015.

Archbishop Terrence Thomas Prendergast of the Archdiocese of Ottawa, was appointed Apostolic Administrator on January 13, 2016, and became Bishop of Alexandria-Cornwall on April 27, 2018, while remaining Archbishop of Ottawa.

On December 12, 2018, Pope Francis named Guy Desrochers as Titular Bishop of Melzi and Auxiliary Bishop of Alexandria-Cornwall (with episcopal ordination to take place in St. Finnan's Cathedral, Alexandria on February 22, 2019).