So far, cases outside of Latin America and the Caribbean, where the Zika virus is prevalent, have been spread by travel to that region or sexual transmission.
The four Florida cases mean US mosquitoes may be carrying the Zika virus.
Zika causes only a mild illness in most people but the virus has been linked to severe brain defects in newborns.
The Florida department of health said “a high likelihood exists that four cases are the result of local transmission”, centered on one small area just north of downtown Miami.
More than 1,650 cases of Zika have so far been detected in the United States, but the Florida cases would be the first in the US not involving foreign travel.
Two of those suffering from the virus are in Miami-Dade county and the other two in neighboring Broward county. They are the most densely populated counties in Florida.
Governor Rick Scott said the cases involved three men and a woman, and that none had been hospitalized.
To confirm whether Zika is being carried by mosquitoes locally, scientists are surveying houses and people within a 150-yard radius of the cases, the flying distance of the insect.
In February, the WHO declared the Zika virus a global public health emergency because of the risk to newborn children.
In severe cases, children can die and babies who survive can face intellectual disability and developmental delays.
Gov. Rick Scott asked all residents of affected areas to get rid of standing water, where mosquitoes thrive, and for residents to wear insect repellent.
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