Police evacuated 115 residents on Wednesday from the facility, whose air conditioning was cut by the storm.
Broward County Mayor Barbara Sharief said three were found dead at the nursing home in the city of Hollywood. Five others died in hospital.
Ten million people are still without power in Florida, Georgia and the Carolinas after Hurricane Irma.
The storm - which has claimed more than two dozen lives in the US - struck southwestern Florida on Sunday morning as a category four hurricane before weakening to a tropical depression on Monday.
Irma earlier left a trail of destruction in the Caribbean, where nearly 40 people were killed.
Hollywood Police Chief Tomas Sanchez said the Rehabilitation Center at Hollywood Hills facility has been sealed off and police are conducting a criminal investigation.
State investigators from the Florida Office of Attorney General were also at the scene, city officials said in a statement.
"It may be related to a loss of power in the storm," Mr Sanchez said, adding that officers were checking in on 42 other assisted living facilities and nursing homes throughout the city.
Florida Governor Rick Scott also ordered emergency workers to check on nursing homes and assisted living facilities to ensure residents are safe.
"This situation is unfathomable," he said.
Hollywood Fire Rescue found several patients "in varying degree of medical distress and immediately began treatment" when they arrived at the Hollywood Hills facility on Wednesday morning, according to the city's statement.
Some residents there awoke sick, the Miami Herald reported.
Kitchen worker Jean Lindor told the newspaper a generator allowed staff to cook but did not provide the facility with air conditioning.
Temperatures on Tuesday in Hollywood reached 32C (90F), according to the National Weather Service.
The nursing home has had brushes with the regulators in recent years for violating federal rules on its power system, a generator and because of a faulty alarm, according to records.
-BBC
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