Sanford sits on the south shore of Lake Monroe at the head of the navigation on the St. Johns River. During the Seminole Wars of the 1830's, the area was the site of an U.S. Army post name Fort Mellon. As settlers moved into the area, the town of Mellonville was established. With the advent of commercial steamboat service, the town became a distribution point for goods essential for the growth of Central Florida. When Orange County was created in 1845, Mellonville became the county seat.

In 1870, Henry Shelton Sanford purchased the land west of Mellonville. He planned a new city "the Gate City of South Forida," which he believed would become the transportation hub for all of southern Florida. In 1877, the city of Sanford was incorporated and Mellonville was annexed six years later. In 1880, Henry S. Sanford formed a land company in London to encourage investments in the new city. That same year construction began on the South Florida Railroad with a terminus in Sanford. By 1884, Sanford was a prosperous town with wharves, a railroad station and a large hotel.

Mr. Sanford's greatest interest in Florida was the development of Belair, a citrus grove and experimental garden near Sanford. More than 140 varieties of citrus, including the Valencia orange, were tested for adaptability to the Florida climate.

In September 1887, a bakery on First Street caught fire. The blaze spread rapidly through the wooden buildings on the east side of town until stopped by the volunteer fire department. When the town was rebuilt, the new structures were made of brick.

During the winter of 1894-95, the citrus industry received a serious blow when freezing temperatures destroyed the year's entire crop. Many citizens faced economic ruin and left the area. Those who stayed harnessed artesian wells and developed a subirrigation system that permitted commercial agriculture. By the first decade of the 20th century, Sanford was one of the largest vegetable shipping centers in the United States, and received the nickname "Celery City" for the most successful crop.

On April 25, 1913, Seminole County was officially established with Sanford as the county seat. In the boom and bust years that followed, Sanford shared in the growth of Central Florida.

From 1942 to 1968, the Sanford U.S. Naval Air Station drew many residents away from agriculture and brought new people to the city. Today the old station is Sanford's International Airport.