Assessing chemical loading from streams in remote, difficult-to-access watersheds is challenging. The Grand Canyon area in northern Arizona, an international tourist destination and sacred place for many Native Americans, is characterized by broad plateaus divided by canyons as much as two-thousand meters deep and hosts some of the highest-grade uranium deposits in the U.S. From 2015–2018 major surface waters in Grand Canyon were monitored for select elements associated with breccia-pipe uranium deposits in the area, including uranium, arsenic, cadmium, and lead. Dissolved constituents in the Colorado River were monitored upstream (Lees Ferry), in the middle (Phantom Ranch), and downstream (Diamond Creek) of uranium mining areas. Concentrations of uranium, arsenic, cadmium, and lead at these main-stem sites varied little during the study period and were all well below human health and aquatic life benchmark criteria (30, 10, 5, and 15 μg/L maximum contaminant levels and 15, 150, 0.8, and 3.1 μg/L aquatic life criteria, respectively). Additionally, dissolved and sediment-bound constituents were monitored during a wide range of streamflow conditions at Little Colorado River, Kanab Creek, and Havasu Creek tributaries, whose watersheds have experienced different levels of uranium mining activities over time. Samples from the tributary sites contained ≤3.8 μg/L of dissolved cadmium and lead, and ≤17 μg/L of dissolved uranium. Dissolved arsenic also was mostly below human and aquatic life criteria at Little Colorado River and Kanab Creek; however, 63% of water samples from Havasu Creek were above the maximum contaminant level for arsenic. Arsenic in suspended sediment was greater than sediment quality guidelines in 9%, 35%, and 35% of samples from Little Colorado River, Kanab Creek, and Havasu Creek, respectively. At the concentrations observed during this study, tributaries contributed on average only about 0.12 μg/L of arsenic and 0.03 μg/L of uranium to the main-stem river. This study demonstrates how chemical loading from mined watersheds may be reliably assessed across a wide range of flow conditions in challenging locations.