The original Romanesque church in the vicinity of Zderaz was consecrated in 1181. After New Town was founded by Charles IV in 1348 the church became one of the parish churches in the town. In the second half of the 14th century the church was rebuilt in Gothic style and it was adapted during the Renaissance and Baroque periods as well. Like the unpreserved adjacent monastery, the church was meant to be torn down in 1890s as part of the urban renewal in Prague, however, the Commission for the List of Architectural, Artistic and Historical Sites of the Royal Capital of Prague managed to protect it from demolition.
Throughout the Hussite wars the church was used by Hussite priests. In 1926 it was bought by the Czechoslovak Hussite Church which administers it still today.
The church played an important role during the events immediately after the assassination of Reich Protector Reinhard Heydrich on 27 May 1942. The local parish clerk Josef Jeřábek was friends with Vladimír Petřek, the chaplain of nearby Sts Cyril and Methodius Church, and helped him to provide clothes, ration cards and food for the parachutists who had carried out the assassination and were hiding in the church of Sts Cyril and Methodius afterwards. Jeřábek was also one of the few eyewitnesses (who did not belong to the troops or firemen) of the struggle for the crypt, the refuge of the parachutists – on 18 June 1942 he watched the action from his hiding place in the skylight of St Wenceslas church.
St Wenceslas Church at Zderaz was damaged during the allied air attack on Prague on 14 February 1945. Josef Sudek documented it with his camera in this state. The restoration works on the church took place in 1947.