The Guadalupe River watershed consists of 170 square miles (400 km2) of land within northern California's Santa Clara County. The surface runoff from this area drains into the Guadalupe River, its tributary streams, reservoirs or other bodies of water which all eventually gets carried into the San Francisco Bay (indicated below, with surrounding counties in red). Essentially, all the water from the creeks and rivers that make up the Guadalupe watershed, including water from storm drains, flows into the Guadalupe River, and then flows downstream into the San Francisco Bay at the Alviso Slough in Alviso. The Guadalupe watershed's main tributaries include Los Gatos Creek, Trout Creek, Hendrys Creek, Ross Creek, Pheasant Creek, Rincon Creek, Herbert Creek, and Golf Creek. Six major reservoirs exist in the watershed: Calero Reservoir on Arroyo Calero, Guadalupe Reservoir on Guadalupe Creek, Almaden Reservoir on Los Alamitos Creek, Vasona Reservoir, Lexington Reservoir, and Lake Elsman on Los Gatos Creek.
The area covered by the Guadalupe River and its tributaries spreads over the neighboring cities of San Jose, Los Gatos, Monte Sereno, Campbell, and Santa Clara.