In 1774, noted botanist William Bartram travelled across what is now the southeastern corner of Alachua County following an old Indian and trading trail. In Florida's territorial period, English-speaking settlers used the same route as a frontier road. By 1840, another road form the north crossed that trail near present day Hawthorne. In 1848, Morrison had begun to operate a mill there on what Bartram had described as a "rapid brook." A United States post office called Morrison's Mills was established at that site in 1853 in order to serve the increasing population of the area.
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In 1879, the Peninsular Railroad was completed from Waldo to Ocala, bypassing Morrison's Mills. In that year, a new town grew up nearer the railroad. This village was at first called Jamestown, but in 1880, the name was changed to Hawthorne. Both names were in honor of James M. Hawthorn, a local landowner. In 1881, the Florida Southern Railway was completed from Palatka to Gainesville, crossing the Peninsular Railroad at Hawthorne. In the 1880's the community there was also known unofficially as Wait's Crossing in reference to another family living in the area. In 1883, a stone quarry near Hawthorne became the site of Florida's earliest phosphate mill. The mill was operated for two years by Dr. C. A. Simmons, who in 1879 had been the first person to recognize phosphate in Florida. However, the most important resources of the Hawthorne area have been its agricultural and forestry products such as sea island cotton and turpentine.