The development of the IS heavy tank series gave the Red Army a superior self-propelled platform to mount the fearsome 152mm ML-20 gun. This resulted in the ISU-152 (Istrebitelnaja Samokhodnaya Ustanovka) which kept the SU-152's firepower but with additional armor protection which reached 90mm maximum and retained the sloped front and sides of the SU, although at a slightly less pronounced angle. Other differences were a slightly higher profile for the superstructure, a lower suspension, and also a revised mantlet which was bolted on the right side of the hull. As a result of the ISU-152's thicker armor compared the SU-152, it turned out to be a far superior platform for urban combat and was ubiquitous in the late war sieges of Königsberg, Budapest and Berlin where its massive gun proved excellent against enemy strongpoints. It was also very effective against enemy tanks which allowed it to retain the nickname of Zvierboy ('Animal hunter') that had been previously given to the SU-152. Production of the ISU-152 continued post-war where it was modernized constantly through the fitting of more powerful engines as well as other structural improvements. They were not retired from Soviet service until the 1960s. Other users included Poland, China, Czechoslovakia, North Korea and Iraq.

The initial Ob'yekt 241 prototype began trials in September 1943, shortly after the development of the SU-152 which it was directly based on. Production of the ISU-152 began in December. Wartime production varied little but two series of modernizations took place post-war. The first resulted in the ISU-152K which incorporated the engine of the T-54 and added a cooling system and heater as well as increasing the internal fuel tank capacity and ammunition storage. Structural changes also included a new commander's cupola. Some were also fitted with extra armor. This version was also based on the IS-2 chassis. A final variant was the ISU-152M with night vision sights, improved secondary armament as well as some of the other modifications found in the ISU-125K. Other variants included the Oka with a 406mm gun capable of firing nuclear shells, as well as a platform for FROG medium-range missiles.