In 1539, when Spanish explorer Hernando de Soto led the first European expedition deep into the territory of the modern-day United States, the Apalachee capital was Anhaica (present-day Tallahassee). They were a strong and powerful tribe living in widely dispersed villages. Other tribes respected the Apalachees because they were considered an advanced Indian civilization, they were prosperous, and they were fierce warriors. Their villages were organized around earthwork mounds built over decades for ceremonial, religious and burial purposes.

The name Tallahassee is a Muskogean language word often translated as "old town" or "old fields". It was probably ascribed by the Creek people who migrated to the region from Georgia and Alabama after their own lands were encroached upon by European settlers. At Tallahassee, they found large areas of cleared land previously occupied by the Apalachee tribe.

During the winter of 1539, Hernando De Soto and his men occupied the capital of the Apalachee people in what is now Tallahassee. It is one of the few places on the route where archaeologists have found physical traces of the expedition, and since Christmas was one of the highlights of the medieval Spanish calendar, De Soto's encampment is likely the first place Christmas was celebrated in the continental United States.

During the Great Blizzard of 1899 the city reached -2 °F (-19 °C) on February 13, which remains Florida's only recorded reading below 0 °F (-18 °C).

In 1836, Osceola led a small group of warriors in the Seminole resistance during the Second Seminole War, when the United States tried to remove the tribe from their lands in Florida to Indian Territory west of the Mississippi River. Today, a horse and rider representing Osceola and his Appaloosa horse Renegade introduce home football games by riding to midfield with a burning spear and planting it in the turf.

Friday nights before FSU home games, Adams Street and College Avenue come alive for Downtown Getdown, a community pep rally with live music, food trucks, local art, craft beer and wine, and benefits for charities.

In the early 1820s, legislators conducted government business in St. Augustine and Pensacola during alternating sessions, but travel between the two cities was hazardous and took almost three weeks. Tallahassee was chosen as the state capital of Florida in 1824, primarily because it was the midpoint between the two principal cities.

At the onset of the First Seminole War on March 31, 1818, General Andrew Jackson found Tallahassee abandoned and ordered it burned to the ground. He then moved on to Miccosukee, which had not yet been abandoned, and burned another 300 homes.

The popular college activity known as "streaking" was invented on Tallahassee's FSU campus on January 15, 1974, when three male students stripped down near Tully Gym and sprinted across the tennis courts as Forrest Gump would say, "for no particular reason." Whether they were making a social statement or just having some harmless fun, a new craze was born. But potential streakers beware: the birthday suit streak can lead to an indecent exposure charge and land you on the Sex Offender Registry in many states.

Tallahassee's rolling landscape is unique among the major cities of Florida. Some areas, including the downtown ridge encompassing the Capitol complex, City Hall, and the County Courthouse, exceed elevations of 200 feet--making Tallahassee the hilliest city in Florida.