As groundwater becomes an increasingly important water resource worldwide, it is essential to understand how local geology affects groundwater quality, flowpaths and residence times. This study utilized multiple tracers to improve conceptual and numerical models of groundwater flow in the Middle San Pedro Basin in southeastern Arizona (USA) by determining recharge areas, compartmentalization of water sources, flowpaths and residence times. Ninety-five groundwater and surface-water samples were analyzed for major ion chemistry (water type and Ca/Sr ratios) and stable (¹⁸O, ²H, ¹³C) and radiogenic (³H, ¹⁴C) isotopes, and resulting data were used in conjunction with hydrogeologic information (e.g. hydraulic head and hydrostratigraphy). Results show that recent recharge (<60 years) has occurred within mountain systems along the basin margins and in shallow floodplain aquifers adjacent to the San Pedro River. Groundwater in the lower basin fill aquifer (semi confined) was recharged at high elevation in the fractured bedrock and has been extensively modified by water-rock reactions (increasing F and Sr, decreasing ¹⁴C) over long timescales (up to 35,000 years BP). Distinct solute and isotope geochemistries between the lower and upper basin fill aquifers show the importance of a clay confining unit on groundwater flow in the basin, which minimizes vertical groundwater movement.