A private zoo owner set free dozens of lions, tigers, bears, wolves and other animals before killing himself.
Police were forced to shoot most of them as they wandered the countryside in Zanesville, Ohio over worries they could attack people.
Sheriff Matt Lutz said zoo owner Terry Thompson left the animals' gates open and even cut open their pens so they would get out.
Deputies found Thompson's body when they went to is farm after getting reports of wild animals running free. They spent the night hunting down and shooting most of the nearly 50 animals.
Schools closed and motorists were warned to stay in their vehicles as officers with assault rifles hunted for the remainder. They were under orders to shoot to kill because it was not safe to tranquillise the animals in the dark.
The preserve had lions, tigers, cheetahs, wolves, giraffes, camels and bears. Police said bears and wolves were among the escaped animals that were killed and there were multiple sightings of exotic animals along a nearby road.
Sheriff Lutz called the animals "mature, very big, aggressive" but said a caretaker told authorities the animals had been fed on Monday.
Zoo staff went to the scene, hoping to tranquillise and capture the animals after daybreak. Director Jack Hanna, said that was something that could not be done in the dark.
"You cannot tranquillise an animal like this, a bear or a leopard or a tiger (at night-time). If you do that, the animal gets very excited, it goes and hides, and then we have his (Lutz's) officer in danger of losing their life, and other people."
Ohio has some of America's weakest restrictions on exotic pets and among the highest number of injuries and deaths caused by them.