For much of the county's history, its economy was based on agriculture, particularly cotton plantations, which were established across the uplands.

These plantations and their owners' profits were dependent on the labor of enslaved African Americans before the Civil War.

[6][7] In the 1810 census alone, Madison County made up nearly half of the population in what would become Alabama, though this did not include Native American tribes and their people.

Most labor for cultivation was still provided by African Americans, but they worked as sharecroppers and tenant farmers.

By the late 19th century, textile mills had been established around the county; they were restricted to white workers by the Jim Crow practices of racial segregation.

During the early 20th century, the economy continued to be largely agricultural, although textile mills expanded their production.

During World War II, the Army established Redstone Arsenal here as a chemical weapon manufacturing site, and the county attracted related industries.

In 1950, a group of exiled German rocket scientists, led by Wernher von Braun, came to Redstone Arsenal from Fort Bliss, Texas in order to conduct research and development of new types of rockets.

The US began to emphasize investment in the Space Race, in order to compete with the Soviet Union during the Cold War years and to increase scientific gains.

According to the 2000 census, the largest ancestry groups in Madison County were English 50.2%, African 22.78%, Scots-Irish 8.71%, Irish 4.3%, Scottish 4.12%, and Welsh 2.9%.

Communities served include Hazel Green, Harvest, Meridianville, Monrovia, Moores Mill, New Market, Redstone Arsenal, and Toney.

The Port of Huntsville provides both passenger air service, via Huntsville International Airport which allows access to most of the rest of the United States, and shipping air service, via the International Intermodal Center.

Even in 1964, the county nearly voted against Barry Goldwater due to its opposition to the Arizona Senator's privatization plans for the Tennessee Valley Authority.

For Alabama counties supporting Donald Trump in 2016, it was the fourth narrowest margin, and in 2020 the third-narrowest after Conecuh and Barbour.

[22] In 2020, Violet Edwards made history becoming the first black woman to be elected to the Madison County Commission.

[23] Madison County is home to Monte Sano State Park, the U.S. Space & Rocket Center, and part of the Flint River.