The failure of the human body to thermoregulate can lead to severe outcomes (e.g., death) and lasting physiological damage. However, heat-related illness (HRI) is highly preventable via individual- and community-level modification. A thorough understanding of the burden is necessary for effective intervention. This paper describes the burden of severe HRI morbidity and mortality among residents of a humid subtropical climate. Work-related and non-work-related HRI emergency department (ED) visits, hospitalizations, and deaths among Florida residents during May to October (2005–2012) were examined. Sub-groups susceptible to HRI were identified. The age-adjusted rates/100,000 person-years for non-work-related HRI were 33.1 ED visits, 5.9 hospitalizations, and 0.2 deaths, while for work-related HRI/100,000 worker-years there were 8.5 ED visits, 1.1 hospitalizations, and 0.1 deaths. The rates of HRI varied by county, data source, and work-related status, with the highest rates observed in the panhandle and south central Florida. The sub-groups with the highest relative rates regardless of data source or work-relatedness were males, minorities, and rural residents. Those aged 15–35 years had the highest ED visit rates, while for non-work-related hospitalizations and deaths the rates increased with age. The results of this study can be used for targeted interventions and evaluating changes in the HRI burden over time.