Once mass production of the ISU-152 self-propelled gun began in late 1943 it was realized that the rate of production of 152-mm ML-20 guns would lag that of vehicles that were to mount it. As a result, the ISU-122 was developed to fill this gap in production by using the ISU-152's chassis with the smaller calibre 122-mm A-19 that was more widely available. This pairing proved highly efficient since both guns used the same gun carriage and therefore there was no need for a major redesign of the vehicle's hull or interior. The ISU-122 was therefore visually nearly identical to the ISU-152 sharing the same sloped armor layout that gave much better protection compared to the SU series. In 1944, the gun was replaced in favor of the 122mm D-25S gun, the same used in the IS-2 heavy tank. The ISU-122 was used extensively during the final Soviet offensives in 1944-45, often serving alongside the ISU-152 although in most cases, independent heavy self-propelled artillery regiments were equipped with only one of the two in order to maintain logistical consistency. Both remained in service after the war but the ISU-122 was retired earlier and received a less comprehensive post-war modernization before their retirement in 1960.

The first prototype, known as Ob'yekt 242 and armed with the 122-mm A-19S gun, was completed in December 1943 but production of the ISU-122 began only until April of 1944. In September, the gun was replaced by the D-25S which improved the low rate of fire to 2 or 3 rounds per minute which was still relatively low. These vehicles were known as the ISU-122S (Ob'yekt 249). Post-war uses of the ISU-122 included the same platforms as that of the ISU-152, while existing vehicles were modernized in 1958 with new gun sights and radio sets.