Incorporated as a town on December 13, 1819, it was named after Tuskaloosa, the chief of a band of Muskogean-speaking people who battled and were defeated by forces of Spanish explorer Hernando de Soto in 1540 in the Battle of Mabila, thought to have been located in what is now central Alabama.

Tuscaloosa served as Alabama's capital city from 1826 to 1846. The State House was built at the corner of 6th Street and 28th Avenue (now the site of Capitol Park).

A resident of Tuscaloosa is officially known as a Tuscaloosan.

Tuscaloosa has traditionally been known as the "Druid City" (after an ancient Celtic people who worshipped oaks) because of the numerous water oaks planted in its downtown streets since the 1840s.

Tuscaloosa is the largest city on the Black Warrior River, which is impounded along nearly its entire course by a series of locks and dams to form a chain of reservoirs that not only provide a path for an inland waterway, but also yield hydroelectric power, drinking water, and industrial water.

City leaders adopted the moniker "The City of Champions" after the Alabama Crimson Tide football team won the BCS National Championship in their 2009, 2011, and 2012 seasons.

Drish House was built in 1937 by Dr. John R. Drish at the center of a 450-acre plantation. According to legend, Dr. Drish, who loved gambling and drinking, died in 1867 after falling down a stairway while drunk. His wife, Sarah McKinney, became obsessed with her husband's funeral. She even kept candles from the funeral hoping to use them after her own passing. Her family searched for these candles following her death in 1884 but were unable to find them. This is said to have angered Sarah so much that she returned to haunt the house, even allegedly causing a fire in the third-story tower by lighting the missing candles.

Van de Graaff is a crater formation located on the far side of the Moon, on the northeast edge of Mare Ingenii. The crater is named for Tuscaloosa-born physicist Robert J. Van de Graaff, whose groundbreaking work includes the invention of the Van de Graaff generator.

The city's first traffic light was installed at 15th Street and Hackberry Lane in 1945, followed by the first of 750 parking meters in 1947.

At the time of its construction in 1938, the Bama Theatre was the only air-conditioned building in Tuscaloosa.