Safety Harbor is the home of the historic Espiritu Santo Springs, or "Springs of the Holy Spirit", a natural mineral spring. Its waters were given this name in 1539 by the Spanish explorer Hernando de Soto, who was supposedly searching for the mythical "Fountain of Youth". Prior to the Spanish exploration of Florida, the Tocobaga and Timuquan tribes are believed to have fished and bathed in the spring's waters.

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In the twentieth century, Espiritu Santo water was bottled and sold commercially, and later a health spa and hotel were built over the springs. The Safety Harbor Resort and Spa, as it is now known, continues to be a prominent visitor attraction in Pinellas County. In 1964, the site was designated a Historical Landmark by the U.S. Department of the Interior and, in 1997, a Florida Heritage Landmark.