Heavy metals, a class of persistent environmental toxicants, are harmful to human health. Cd and Pb are two of the most common toxic heavy metals that have been linked with cancers and malfunction of the nervous system. Notably, contamination of Mn usually coexisted with Cd and Pb in environmental and occupational settings. Studies regularly examined the toxic effects on individual metals; however, potential health and toxic effects of mixtures containing two or more heavy metals are unknown. Here, we investigated toxic effects of Cd, Pb, Mn, and their binary and ternary mixtures in the nematode Caenorhabdities elegans. The toxic outcomes, including effects on growth, reproduction, and feeding, were measured via high-throughput platform analysis. The transgenic strain BY250 with GFP in dopaminergic neurons was used to explore the neurodegenerative effects induced by single metals or their mixtures. The combination index(CI) for mixtures effect was calculated using isobolograms methods. Following the exposure, we found significant toxic effects in C. elegans. For single metals, the toxicity order for growth, reproduction, and feeding were Pb > Cd > Mn. For mixtures, the mixture of Cd + Mn induced a less than addictive effect in C. elegans, whereas the mixtures of Cd + Pb, Pb + Mn, and Cd + Pb + Mn induced greater-than-additive effects. Both single metals and their mixtures induced abnormality in dopaminergic neurons. These results showed combinative toxic and neurodegenerative effects of heavy metal mixtures, and future studies will focus on characterization of concentration-response patterns and identification of potential molecular mechanisms in C. elegans model.