After the purchase of the Florida Territory, settlement was delayed while the native Indians were cleared from the area in a bloody eight year war. Discussions were held about selling the panhandle region to the Republic of Alabama, but local resistance allowed it to remain a part of the Florida Territory.

During the American Civil War, the area became important to the South for the salt and fish it produced to feed the Conferate soldiers. The Union captured the area in 1862, and after two Union soldiers were killed, Old Town St. Andrew was burned to the ground by Federal troops. The area remained in Union control until after the War's end and well into the Reconstruction Era.

The natural harbor and the abundance of fish in the area caused the town to be rebuilt after the war. The area's first sawmill was built on the north shore of the Bay in 1885 and land was sold in the area for 1$ per acre. The city was formed in 1905 from unincorporated lands and named Panama City in a effort to get the United Fruit Company of New Orleans, whose major source of fruit was Panama, to relocate to the area.

Despite not getting the fruit company to relocate, Panama City prospered, and in 1906 the founder of Coca Cola, Asa Candler, donated money to complete the railroad line from Atlanta to Panama City. The nearby town of Lynn Haven attracted many Civil War Veterans to the Area, calling it the "Magic City." The Gulf Coast Highway (US 98) was completed in the 1930's, as well as three bridges connecting the beaches to Panama City.

During World War II, Panama City got another boost to its economy when the Army opened an aerial gunnery school named Tyndall Field. One of the officers who trained here was the famous actor, Clark Gable. The War Department also established a small shipyard in the bay for the construction of Liberty Ships, eventually building 102 of the ships during the war. Since the end of the War, Panama City has established itself as a holiday vacation destination that draws millions of visitors each year.