During the Soviet period many Slutsk Jews worked as merchants or artisans, while others engaged in agriculture. In the 1930s, when private trade was banned, most local Jews became government workers or craftsmen. In the 1920s Slutsk had three seven-year Yiddish schools with a total of 700 pupils. Later the number of Yiddish pupils decreased until the last Yiddish school was closed in mid-1938, as was the whole Yiddish school system in Belarus.
Soviet militant anti-religious policy led to the decline of religious activity. In the 1920s the building of the Ets Haim Yeshiva was confiscated and the Yeshiva's head, Rabbi Meltser, and his pupils fled to Poland. In the late 1920s and early 1930s the synagogues were closed down; the largest of them, the Kalte Shul was turned into a bakery.
Due to migration to larger cities the Jewish population of Slutsk decreased steadily in the 1920s and 1930s. In 1939 7,392 Jews remained in the town, comprising 33.7 percent of the total population.
The Germans occupied Slutsk on June 27, 1941. The persecution and murder of Jews began almost immediately. The Jews were required to register and a Judenrat was established. The wearing of yellow Stars of David became compulsory. The Jews were taken for forced labor, abused, and killed. The Germans erected four buildings on Bogdanovich Street using as foundation tombstones (matzevahs) from the Jewish cemetery.
On October 27-28, 1941 the first major mass murder of Slutsk Jews took place. At the end of 1941-beginning of 1942 two ghettos were established: the "field ghetto" (on the northern outskirts of Slutsk) where Jews unable to work were imprisoned, and the "town ghetto" for working Jews (situated in the old Jewish quarter of the town, Shkolishche), closer to the town center. The "field ghetto" was gradually liquidated in the spring of 1942. On February 8, 1943 the Germans liquidated the "town ghetto."
Slutsk was liberated by the Red Army on June 30, 1944.