Rio Sonora watershed and its aquifer-located in northwest Mexico-have been influenced by mining operations for 140 years, possibly causing emissions of potentially toxic elements (PTE) and affecting health of exposed populations. On the basis of available data from governmental surveys (2014–2017) and recent sampling (2018), this study constructed reliable PTE total concentration database that allowed us to report temporal/spatial variations in surface and groundwater and their associated health risks to the population living in the central part of the Rio Sonora basin. The data clearly showed that a mining spill that took place in 2014 has had an adverse impact on total PTE concentrations in surface water. They also indicated the presence of different PTE point source locations that have continued to cause contamination of surface water at levels of health concern. Data also suggested slight impacts of the spill event on groundwater possibly related to soil neutralizing potential. Two metal groups were detected for surface waters (Pb–Cd–As–Ni–Cr and of Zn–Al–Cr) and groundwaters (Cr–As–Cu–Cd and Zn–Al), which suggest that they have different sources or are being released by different processes. The potential health impacts of PTE concentrations were associated with specific age groups, dates, and areas. The results indicate that in this complex semi-arid rural system, current and historical mining activities, as well as contrasting hydrological conditions, have impacted surface and groundwater quality with important ecological and human health risks.