We performed synoptic sampling of a 95‐km reach of the San Pedro River, Arizona, to identify the effects of regional hydrology and land use on dissolved carbon and nitrogen concentrations. Six synoptic surveys, two before, two during, and two after the 2002 monsoon season, encompassed periods of both low and high stream discharge. Chloride concentrations and δ18O values during low‐flow periods indicated the river was divided into three hydrologically distinct reaches each roughly 30 km long. Upper and lower reaches were characterized by areas of localized groundwater input followed by downstream evapo‐concentration gradients, limited downstream solute transport, and highly variable carbon and nitrogen concentrations. In contrast, the middle reach was characterized by widespread groundwater input, continuous downstream hydrologic connectivity, and less variable carbon and nitrogen concentrations. During the monsoon season, base flow discharge increased five‐ to ten‐fold, dissolved organic matter and inorganic N increased two‐ to ten‐fold, Fluorescence Index (FI) values indicated a large input of terrestrial solutes, and both chloride concentrations and δ18O values indicated that stream water and alluvial groundwater were well mixed along the entire 95 km reach. Concurrently, the middle reach that exhibited continuous hydrologic connectivity during the nonmonsoon season was a net sink for N, while the reaches characterized by limited hydrologic connectivity during the low‐flow season exhibited net N export. Our data suggest that instream biogeochemical cycling during the monsoon season is influenced by antecedent conditions, specifically hydrologic connectivity, during the dry season.