Sir Robert Beaumont, the primary financier of the railroad project, is furious because his railroad is not being completed on schedule. He has sought out the expertise of Patterson, a military engineer, to get the project back on track. Beaumont tells Patterson that if he doesn't get the bridge built on time, Beaumont will use all of his power and influence to destroy Patterson's reputation as an engineer.
Patterson travels by train to the outpost station, where he is enthusiastically greeted by camp supervisor Angus Starling. When they arrive in Tsavo, Starling introduces Patterson to the first team supervisor, Samuel (the movie's narrator). Samuel is one of the few men at the work site who is respected and trusted by everyone. Patterson also meets the camp's doctor, David Hawthorne, who tells the colonel that he's brought bad luck with him. The doctor shows him a man who was attacked by a lion. The colonel assures the doctor that he will "sort it out". That night, Patterson kills a lion using only one shot from his .303 Enfield rifle. This raises the camp's morale. However, not long afterwards Mahina, the construction foreman, is dragged from his tent in the middle of the night. His half-eaten body is found the next morning. Patterson then attempts a second night-time lion hunt, but the next morning another worker is found dead at the opposite end of the camp from Patterson's position.
Later, a huge male lion attacks the camp, creating panic among the workers and capturing one of them. Patterson, Starling, and Samuel run down the lion and find it feeding on the dead worker. Patterson is about to shoot it when a second lion attacks them and kills Starling. Both lions escape.
Shortly afterwards, Beaumont, who has come to Africa to find out why the railroad is not making any progress, says he will contact a big game hunter known as Remington to get the job done. That evening Patterson attempts to trap the lions in a modified box car, but the workers who are supposed to kill the lions are too scared to do it properly.
Remington arrives, bringing with him some skilled Maasai warriors to help hunt the lions. The men spend all night preparing themselves for the hunt. The hunt goes badly when a rifle Patterson has borrowed from Dr. Hawthorne misfires, almost resulting in his death. Believing the lions are supernatural, the Maasai warriors abandon Remington to hunt the lions on their own. That evening Remington and Patterson take up a watch in the camp's old hospital which they have cleared of patients and doused with blood in an effort to lure the lions. However, the lions attack the new hospital and kill both the patients and Dr. Hawthorne. The entire population of workers evacuate the camp the next day, leaving Patterson, Remington and Samuel behind to deal with the lions.
Patterson and Remington set off towards the mountains and at last successfully locate the lions' den, which they find filled with piles of human and animal remains. Horrified, they conclude that the lions are killing people for "the pleasure" of it and hoarding the skeletons as trophies. The next evening, Patterson waits on a high wooden platform in a clearing, hoping to attract the lions with a captive baboon tethered to a pole on the ground, while Remington and Samuel keep watch from positions around the edge of the clearing. Remington succeeds in killing one lion, and the three men celebrate by getting drunk. Awakening the next morning, Patterson and Samuel discover that Remington has apparently been dragged from his tent and killed by the remaining lion during the night. Grief stricken over Remington's death and now desperate to end the bloodshed, Patterson decides to burn the tall grass surrounding the camp in order to drive the lion towards the camp where he hopes to ambush it.
Patterson and Samuel are soon attacked by the beast on the partially constructed bridge. Patterson shoots and wounds the lion with a howdah pistol. But the lion quickly retaliates, knocking Patterson's weapons away and chasing him off the bridge. Patterson and Samuel manage to climb into two separate trees, but when Patterson looks down he is shocked to see the lion climbing up the tree after him. Samuel tries to throw Patterson his own rifle but it falls to the ground. Patterson jumps from the tree and retrieves the rifle just in time to shoot the lion as it leaps down to kill him.
At the end of the film, Patterson greets his wife and son at the Tsavo station. The final moments of the film have Samuel explaining that the lions are now on display at the Field Museum in Chicago, Illinois and that even today "if you dare lock eyes with them, you will be afraid."