Multi-element concentrations (Al, As, Cd, Cr, Hg, Ni, Pb, Se, and Sr) were analyzed in the muscle of six fish species (Hoplias malabaricus, Oligosarcus jenynsii, Rhamdia quelen, Bryconamericus iheringii, Astyanax fasciatus, and Odontesthes bonariensis) with different diets and habits from the Río Tercero Reservoir (RTR) in Córdoba, Argentina, during the wet and dry seasons. Besides, potential human health risks, associated with the consumption of these elements, have been assessed considering the average daily intake (EDI) in children and adults. Additionally, the target hazard quotient (THQ) and carcinogenic risk (CR) were evaluated taking into account the intake by the general population, fishermen, and consumption frequency recommended by the American Heart Association (AHA), the maximum scientific reference in cardiology in the USA and worldwide. All species presented quantifiable values in muscle for all the analyzed elements (Al, As, Cr, Hg, Ni, Se, and Sr), except for Cd and Pb, being Al and Sr the most accumulated elements in all species in both seasons. The consumption of edible muscles of the species studied in this reservoir represents a toxicological risk to humans. Mercury and As were the main elements that presented a health risk through the consumption of fish. Their concentrations in most fish species were above the maximum daily allowable concentrations, and THQ values were several times greater than 1. In addition, according to AHA recommendations, the cancer risk caused by As was greater than the acceptable value of 10⁻⁴ in all species studied, and in both seasons, with the exception of A. fasciatus, in the rainy season. These results indicate that the consumption of fish from the RTR exposes the inhabitants to possible health risks, especially when considering the consumption frequency recommended by the AHA. Therefore, fish intake from this reservoir should be limited to minimize potential risks to the health of consumers. Finally, the results of this study are useful for controlling pollution and developing preventive and palliative policies to protect populations in contact not only with the reservoir but also with other areas of the world with similar conditions.