Syria had been deeply involved in Lebanon’s Civil War since 1976. A Jihadist splinter group from the Muslim Brotherhood took advantage of this situation to start an armed rebellion against the government of Hafez al-Assad. The Muslim Brotherhood opposed Assad on political as well as theological grounds; Assad was an Alawite, regarded as heretical by the hardline Sunni Islamists.

Events culminated with a general insurrection in the conservative Sunni town of Hama in February 1982. Islamists and other opposition activists proclaimed Hama a "liberated city" and urged Syrians to rise up against the "infidel". Brotherhood fighters swept the city of Ba’athists, breaking into the homes of government employees and suspected supporters of the regime, killing about 50.

The army was mobilized, and Hafez sent Rifaat’s special forces and Mukhabarat agents to the city. Before the attack, the Syrian government called for the city’s surrender and warned that anyone remaining in the city would be considered a rebel. Robert Fisk in his book Pity the Nation described how civilians were fleeing Hama while tanks and troops were moving towards the city’s outskirts to start the siege. He cites reports of high numbers of deaths and shortages of food and water from fleeing civilians and from soldiers.

According to Amnesty International, the Syrian military bombed the old city center from the air to facilitate the entry of infantry and tanks through the narrow streets; buildings were demolished by tanks during the first four days of fighting. They also claim that the Syrian military pumped poison gas into buildings where insurgents were said to be hiding. After encountering fierce resistance, Rifaat’s forces ringed the city with artillery and shelled it for three weeks. The Syrian army assaulted the town of 350,000 people on February 2 with extensive shelling.

Afterwards, military and internal security personnel were dispatched to comb through the rubble for surviving Brothers and their sympathizers. Torture and mass executions of suspected rebel sympathizers ensued, killing many thousands over several weeks. Estimates of casualties vary from an estimated 7,000 to 35,000 people killed, including about 1000 soldiers; Robert Fisk, who was in Hama shortly after the massacre, estimated fatalities as high as 10,000, whereas the New York Times estimates death toll as up to 20,000. According to Thomas Friedman, Rifaat later boasted of killing 38,000 people. The Syrian Human Rights Committee estimates 30,000 to 40,000 people were killed. Most of the old city was completely destroyed, including its palaces, mosques, ancient ruins and the famous Azem Palace mansion.