In suburban Nebraska, a group of partying high school teens jokingly dare their friend Charlie to look into the mirror and repeat "Bloody Mary, Bloody Mary, Bloody Mary," not knowing this will unleash a series of mysterious murders. Sam and Dean realize that Bloody Mary has the power to travel through all reflective surfaces when she is hunting a victim. Worried that teens are accidentally summoning Bloody Mary, Sam and Dean race to destroy the violent spirit before she can kill again.

Sam and Dean head to Minnesota where a young boy witnesses a man vanish into thin air. Upon searching for clues, Sam is abducted by what he assumes is a supernatural being, and Dean is left to search frantically for his brother. However, both are stunned when they realize the kidnappers are human, and using the captives as human prey for a twisted hunting expedition.