The upper part, in the Texas Hill Country, is a smaller, faster stream with limestone banks and shaded by pecan and bald cypress trees.

Ahead of the entry into the San Antonio Bay estuary, it forms a delta and splits into two distributaries referred respectively as the North and South parts.

It was renamed the San Augustin by Domingo Terán de los Ríos who maintained a colony on it, but the name Guadalupe persisted.

Evidence indicates that it has been home to humans for several thousand years, including the Karankawa, Tonkawa, and Huaco (pronounced like Waco) Indians.

Being led by Prince Solms, 228 pioneer immigrants from Germany traveled overland from Indianola to the site chosen to be the first German settlement in Texas, New Braunfels.

On the night of July 16 and into the morning of the 17th, almost 12 inches (300 mm) of rain had fallen across the Texas hill country to the north, triggering immense flooding on the Guadalupe River.

Rescuers from the Texas Department of Public Safety and the US Army's 507th Medical Division managed to save all four adults and twenty-nine of the children via helicopters.

The first confirmed fatality was 14-year-old Melanie Finley, who after being lifted from the river by helicopter lost her grip on the rope and fell to her death.

[13] In the summer of 1988, near the edge of the river and at the foot of the driveway to the Pot O' Gold Ranch, a memorial plaque was dedicated to the children who died as well as those who survived.

During the rainy seasons the water can reach well above the banks and exceed "normal" levels, in which case it can become life threateningly dangerous due to swift currents.

If the flow gauge exceeds 1,000 cubic feet per second (28 m3/s) at the Sattler Gage, it is generally considered by local authorities as too dangerous for recreational purposes for all except expert kayakers and/or whitewater rafters.

On October 31, 2013, the part in New Braunfels rose from 74 to 33,500 cubic feet per second (2.1 to 948.6 m3/s) in one hour and fifteen minutes due to locally heavy rainfall.