In Ontario, Canada, the radio host of a talk show in the morning in Pontypool town, Grant Mazzy, works with his producer Sydney Briar and the technician Laurel-Ann Drummond. One snowing morning, the journalist Ken Loney reports that a violent crowd is trying to invade the office of Dr. Mendez downtown. Then the radio receives confused information about a possible infection in Pontypool by witnesses. Out of the blue, a crowd tries to overrun the radio station and Dr. Mendez breaks in the window. Grant, Sidney and Dr. Mendez note that Laurel is infected, and they lock themselves in Grant's soundproof cabin to seek protection. Suddenly, Dr. Mendez finds that the virus outbreak is caused by words spoken in English.

When police officer Carter (Aaron Poole) discovers a blood-soaked man limping down a deserted road, he rushes him to a local hospital with a barebones, night shift staff. As cloaked, cult-like figures surround the building, the patients and staff inside start to turn ravenously insane. Trying to protect the survivors, Carter leads them into the depths of the hospital where they discover a gateway to immense evil.