Humans and wildlife are frequently exposed to complex mixtures of chemicals, with exposure rarely causing only one dominant effect. Consequently, there is an urgent need to develop strategies to assess exposures to multiple, hazardous chemicals and effects of such combinations. Here, the maximum cumulative ratio was used as part of a tiered approach to evaluate and prioritize risks of co-exposures to metals in 781 samples of surface water from Tai Lake, China. Multiple metals, including copper, lead, cadmium, nickel and zinc dominated the hazardous effects on aquatic organisms. Based on species sensitivity distributions developed from genus mean chronic values, crustaceans were the most susceptible to effects of metals. Results of a multi-generation experiment demonstrated adverse effects of mixtures of metals at environmentally relevant concentrations on growth and reproduction of the cladocerans, Daphnia magna and Moina macrocopa. Specifically, when exposed to metals body length and total number of offspring produced per adult female were less than the controls. Resistance of D. magna populations to mixtures of metals was significantly less, while, under similar conditions, M. macrocopa exhibited greater capacity to recover and the response to adverse effects occurred earlier. Demographic analysis models constructed using a Leslie matrix, used to predict population dynamics of the cladocerans, revealed that various effects of metal cocktails on individual-level endpoints was related to attenuation at the population level. By integrating all the observations, it was recommended that densities of populations of cladocerans in surface waters could be a useful parameter for indicating possible detrimental effects induced by toxic chemicals. Results of this study provide novel insights into risks posed by simultaneous exposure to multiple metals and reveal their potential adverse long-term effects on sensitive aquatic organisms.