The original church was founded by Władysław Jagiełło in 1392. In 1657, the parish was handed over to the Jesuit Order, who after 1696 started building a new oriented church in the Baroque style with the funds of the guardian father Aleksander Żardecki/Zardecki. Construction was completed in 1709. The interior furnishings were funded by Wiktoryn Kuczyński, the castellan of Podlasie. It was consecrated on January 10, 1723 by the bishop of Łuck, Stefan Bogusław Rupniewski. In the 18th century, the provincial and land councils of the Podlasie nobility were held in the church. After the dissolution of the Jesuit order in 1773, the parish was handed over to the Piarists in 1781.
The church was destroyed during World War I in 1914-1918 and rebuilt in 1919. Again, the church was seriously devastated in the spring of 1940 by the Soviet army. 14 altars, oak confessionals and pews, a Baroque pulpit, epitaphs of the local nobility and numerous paintings were destroyed. A special loss was the destruction of the main altar, which has not been restored to this day. Another damage was done by the Germans in 1941–1944. Partially restored after 1945.
In 1991, the church became the cathedral of the Drohiczyn diocese.