Monroe County Sheriff's Deputy Bryan Cross said he saw the big snake around 11 p.m. Friday as it slithered over the Overseas Highway near the 105 mile marker, the South Florida Sun Sentinel reported.
The deputy followed the reptile into a woods and called the Florida Fish and Wildlife Conservation Commission.
FWC Officer Robert Dube told the newspaper officers were able to find and wrestle the python into captivity, but it wasn't easy.
"This one was particularly nasty," Dube told the newspaper, adding it snapped at the officers as they captured it. "It was nobody's pet."
The report said snake will be killed and a necropsy will see what it had been eating.