<p>Environmental toxic heavy metals seldom exist in isolation. Lead (Pb), cadmium (Cd), and arsenic (As) often co-occur as complex pollutant mixtures, resulting in prolonged combined human exposure through multiple pathways. While traditional toxicological research has largely focused on the effects of individual metals, accumulating evidence indicates that the neurotoxicity induced by co-exposure is not necessarily additive. Indeed, it often manifests as synergistic or antagonistic, involving complex mechanisms that disrupt neural signaling pathways. Thus, investigating their combined effects is essential for achieving more realistic and accurate health risk assessments. This review systematically elucidates the mechanisms by which Pb, Cd, and As both individually and in combination disrupt key signaling pathways in the central nervous system (CNS). Although these metals exert distinct properties, they all induce oxidative stress, disrupt intracellular calcium homeostasis, cause mitochondrial dysfunction, and trigger neuroinflammation to impair neural signaling. Taken together, given the complexity of real-world human exposure scenarios, transitioning from single-metal studies to combined exposure research represents both an urgent need and an inevitable trend in environmental toxicology. Deepening our understanding of the mechanisms underlying their combined toxicity will not only enable more accurate health risk assessment but also provide a critical foundation for the development of science-based public health interventions and the identification of effective neuroprotective targets.</p>