Breccia pipe deposits of the Grand Canyon region contain ore grade copper and uranium. Horn Creek is located near the Orphan Mine mineralized breccia pipe deposit, and groundwater emerging from the bedrock in the headwaters of Horn Creek has the highest uranium concentrations in the region. Uranium decreases an order of magnitude between the groundwater at the top of the watershed and the groundwater emerging from the alluvial material lower in the watershed. Horn Creek water has low sulfur and uranium isotopic ratios which may suggest interaction with sulfide and uranium minerals found in mineralized breccia pipe deposits. Per- and polyfluoroalkyl substances were found in low concentrations in groundwater from the bedrock and may be related to mining process materials or other anthropogenic activities. PHREEQC modelling suggests that water that is elevated in uranium emerging from the bedrock in the upper watershed may mix with other groundwater and atmospheric precipitation infiltrated into the alluvial material in the lower watershed. Tritium is elevated in Horn Creek groundwaters, suggesting a component of modern water, some of which may have interacted with Orphan Mine workings. Additional studies could build on this understanding of chemistry changes in the waters of Horn Creek to provide more direct evidence of the contribution of water moving through the Orphan Mine. Supplementary material: Chemical data for this paper are available at https://doi.org/10.5066/F7P55KJN , PHREEQC geochemical simulations are available at https://doi.org/10.5066/P9X17FKG and groundwater chemistry from south of Grand Canyon, AZ is available at https://doi.org/10.6084/m9.figshare.c.6747638 Thematic collection: This article is part of the Geochemical processes related to mined, milled, or natural metal deposits collection available at: https://www.lyellcollection.org/topic/collections/geochemical-processes-related-to-mined-milled-or-natural-metal-deposits