The upper Guadalupe is popular as a tubing destination where recreational users often float down the river on inflated tire inner tubes during the spring and summer months. East of Boerne, on the border of Kendall County and Comal County, the river flows through Guadalupe River State Park, one of the more popular tubing areas along the river.

The lower river begins at the outlet of Canyon Lake, near New Braunfels. The section between Canyon Dam and New Braunfels is the most heavily used in terms of recreation. It is a popular destination for whitewater rafters, canoeists and kayakers. The flow varies according to the seasons, and by the amount of rainfall the area has received. It is joined by the Comal River in New Braunfels and the San Marcos River about two miles west of Gonzales. The Guadalupe below the San Marcos River is part of the course for the Texas Water Safari.

The San Antonio River flows into the Guadalupe River near the Gulf of Mexico. In San Antonio Bay the Guadalupe River forms a delta and splits into two distributaries, called the North Guadalupe River and the South Guadalupe River.