Niagara Regional police say the baby's parents alerted the hotel about the incident at 10 a.m. on Tuesday.
Police say a maintenance worker removed the crying baby from the safe.
Officers say the parents were at the scene but they left the hotel before police arrived.
There is no information about why the baby was locked in the safe.
Investigators say the hotel room was registered to a person from Brooklyn, N.Y., who was driving a grey passenger van with the New Jersey license plate B31 EUB.
They say they want to locate the family to find out about the welfare of the child.
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