Indigenous paleo-Indian hunter-gatherers were the first inhabitants of the area, thousands of years before European colonization.

Later, historic Indian tribes settled in the area, including Tonkawa, Karankawa, Kickapoo, Lipan Apache, and Comanche.

In 1806, French army officer José de la Baume, who later joined the Spanish army, was rewarded for his services to Spain with title to 27,000 acres (11,000 ha) of Texas land, the original El Capote Ranch.

[5] Following Mexico's independence from Spain, Anglo-Americans from the United States settled in Texas in 1821, and claimed Mexican citizenship.

In 1825, Guadalupe County was part of Green DeWitt's petition for a land grant to establish a colony in Texas, which was approved by the Mexican government.

[4] Following Texas' gaining independence from Mexico (1836), 33 Gonzales Rangers and Republic veterans established Seguin.

Founded as Walnut Springs in 1838, the settlement's name was changed to Seguin the next year to honor Juan Nepomuceno Seguín, who had fought for independence.

In 1845, Prince Carl of Solms-Braunfels secured title to 1,265 acres (512 ha) of the Veramendi grant in the northern part of the former judicial county.

[4] Following the annexation of Texas by the United States (1845), Prussian immigrant August Wilhelm Schumann arrived on the Texas coast aboard the SS Franziska in 1846, and purchased 188 acres (76 ha) in Guadalupe County.

[4] In 1846, during the war between the United States and Mexico, a wagon train of German immigrant settlers bought Guadalupe land from August Schumann.

[4] By 1860, 1,748 slaves of African descent were in the county, generally brought in from the South by slaveholder migrants.

By 1982, professional and related services, manufacturing, and wholesale and retail trade involved nearly 60% of the workforce in the area.

Guadalupe County Fire Rescue was established to augment and assist the volunteer departments with responses due to the increasing volume of emergencies.

These volunteer departments are required to have a first responder organization license through the State of Texas, as well as a certain amount of training hours per year.

The only Democratic presidential candidate to carry Guadalupe County since 1940 has been Hill Country native Lyndon B. Johnson during his 1964 landslide.