Regional stream and pond sediment, panned concentrate, and water sampling at and around known mineral occurrences in the Tyonek quadrangle, Alaska Range, Alaska were undertaken to determine geochemical signatures in the different media. For sediment samples, two different size fractions (− 80 mesh and − 230 mesh) were analyzed. Elevated concentrations (mostly ~ 2 × median) of elements such as As, Au, Cd, Cu, Mo, Pb, and/or Zn were measured in both size fractions in streams draining known occurrences as well as from several other locations. Gold, molybdenite, arsenopyrite, and/or Cu minerals identified in panned concentrates explain some of these elevated values. Water samples from most stream, pond and seep sediment sample sites were analyzed by high-resolution ICP-MS methodology. Relative high concentrations of constituents (including Mo, Re, As, Tl, and/or Cu and/or SO₄) were commonly measured in waters where high metal concentrations were also measured in corresponding sediments and/or heavy mineral concentrates. However, water chemistry yielded higher contrast of upper quartile and anomalous groups relative to median values than observed in sediments. Elevated As, Mo and/or Re probably relate both to deposit mineralogy and the higher solubility of these metals (compared to that of Cu, Pb, Zn) under the predominantly oxidized and near-neutral pH conditions. Our pilot study indicates that, despite large input of snowmelt and very low absolute concentrations (μg/L), water chemistry can be useful for delineating sulfide-bearing mineral occurrences in this region.