The community was destroyed in the Khmelnitsky massacres. 600 local Jews were murdered in 1648 by the Cossacks, with the aid of local Christians. Another 300 were killed a year later, following the return of some of the Jewish fugitives to the town. By the 18th century, the community had regained its prominence. By 1897, under the rule of the Russian Empire, the community had tripled in size, comprising 62 percent of a total population of 14,749. Jews were particularly active in the lumber and cattle trade, and in the sale of agricultural produce.
After World War I, Ostróg was incorporated into the Second Polish Republic. In 1921, the town was home to 7,991 Jews, who made up approximately 62 percent of the total population.
In the interwar period, the Jews of Ostróg engaged in crafts, exported agricultural produce, and manufactured haberdashery, fabrics, and iron. The local Jewish community ran a hospital, a pharmacy, and an orphanage. A branch of TOZ in the town looked after schoolchildren's health and sponsored summer camps for youngsters from poor families. The town had a Tachkemoni Hebrew-language religious school, a Talmud Torah, two Yeshivot, schools and kindergartens affiliated with the Hebrew-language Tarbut system and the Yiddish-language CYSHO system, as well as two Jewish libraries. From 1936, youths could also attend a Tarbut high school. Zionist political parties and their youth movements (e.g., Hashomer Hatzair, Beitar, and Gordonia) were all active in Ostróg, and the town had a HeHalutz pioneer training commune. The Bund party was also present in the town until the early 1930s.
After September 17, 1939, in the aftermath of the Molotov-Ribbentrop Pact, the Red Army entered the town, and Ostróg became part of Soviet Ukraine. Under Soviet rule, a former Bund activist named Motl Gorin served as the mayor of Ostróg. Some affluent Jews and former activists of the Zionist parties, who were categorized as "bourgeois" by the Soviet authorities, were deported from Ostróg to Siberia.
In the wake of the German invasion of the USSR on June 22, 1941, some 1,000 Jews from Ostróg were able to flee eastward. Some of them were conscripted into the Red Army, while others escaped on their own, or were evacuated into the Soviet interior along with the authorities.
On June 28, 1941, German forces occupied the southern part of the town, but Soviet troops continued to hold its western part (which lay close to the former Soviet border). The town was badly damaged in the fighting.
The Germans fully occupied Ostróg on July 3, 1941. In the summer and fall of 1941, the German authorities implemented a number of anti-Jewish decrees in the town. During the first days of the occupation, all Jews aged 16-60 were ordered to report for work (under pain of death). Men were forced to clear the streets of rubble and dead bodies, wash military vehicles, and perform other menial tasks, while the women were ordered to clean German offices, etc. A Jewish council (Judenrat) was set up. The Jews were ordered to wear distinguishing symbols, such as the Star of David (later replaced with a yellow patch), and they were forbidden to leave the boundaries of the town.
In August 1941, units subordinated to the 213rd German Security Division confiscated more than 64 kilograms of ritual items from the synagogues and prayer houses in Ostróg.
On August 4, 1941, between 1,000 and 3,000 Jews, primarily sick and elderly individuals, were shot dead by an SS unit, with the assistance of the Ukrainian Auxiliary Police, in the Ostróg Forest just outside of town, near its new section.
On September 2, 1941, as many as 2,500 Jews, mostly young men and women, were shot dead in the forest near the town of Netishin in the Slavuta County, the Kamenets-Podolsk District.
Shortly after the September massacre, the Germans ordered the establishment of a new Judenrat, since the members of the first one had all been killed in these two murder operations. Avraham Komendant was appointed chairman. A Jewish police force was later organized, as well.
In June 1942, the Jews of Ostróg were relocated to a ghetto; non-Jews had been evicted from the area of the town that had been most severely damaged by the bombing, and the Jews were concentrated in it. The area was then surrounded with a tall barbed-wire fence. At this point, there were approximately 3,000 Jews remaining in Ostróg.
On October 15, 1942, the Ostróg Ghetto was liquidated, and its 2,000 inmates were shot dead in the Ostróg Forest by an SS murder squad, which was assisted by the Ukrainian Auxiliary Police and the German Gendarmerie.
In the second half of October 1942, some 1,000 Jews, who had managed to hide or escape during the liquidation of the ghetto and were later recaptured by the Ukrainian police and the German Gendarmerie, were shot dead at the Jewish cemetery in the town.
Ostróg was liberated by the Red Army on February 5, 1944.