Lead (Pb), mercury (Hg), and cadmium (Cd) are highly neurotoxic, particularly to the developing central nervous system. These metals persist in ecosystems due to their non-degradation feature, bioaccumulating through food chains to cause sustained low-level exposure in the general population. Our preliminary studies demonstrate that even low levels of Pb, Hg, and Cd co-exposure during pregnancy and lactation can result in persistent cognitive impairments in offspring. Although chelation therapy is the clinical standard for acute heavy metal poisoning, its utility in preventing low-dose, mixed-metal neurodevelopmental toxicity is limited by narrow therapeutic windows and potential side effects. This critical gap underscores the urgency to identify safe and effective bioactive nutritional compounds targeting metal neurotoxicity during critical neurodevelopmental windows. To address this gap, we first developed an in vitro screening platform using primary hippocampal neurons and acute hippocampal slices to evaluate the efficacy of bioactive compounds against low levels of Pb, Hg, and Cd co-exposure-induced synaptic plasticity dysfunction. From a panel of four candidates—methionine, choline, vitamin C, and curcumin—selected based on their neuroprotective potential, only methionine significantly attenuated heavy metal-induced synaptic plasticity dysfunction, whereas the others exhibited no noticeable effects. Then, we established an in vivo model using pregnant rats exposed to low levels of Pb, Hg, and Cd to assess whether methionine administration during pregnancy alone or during both pregnancy and lactation could mitigate cognitive impairments in offspring. Notably, methionine intervention restricted to pregnancy was more effective than prolonged (pregnancy + lactation) supplementation in ameliorating deficits in cognitive recognition and spatial memory induced by Pb, Hg, and Cd co-exposure. As the sole sulfur-containing essential amino acid and a critical methyl donor, we found that methionine not only alleviated cognitive deficits but also reversed the elevated levels of hippocampal ten-eleven translocation protein 3 (TET3) induced by Pb, Hg, and Cd co-exposure. These findings suggest that methionine's protective effects may be mediated through the regulation of TET3, a key demethylase involved in synaptic plasticity and cognitive function. To elucidate the underlying mechanisms of methionine's protective effects, we further investigated the role of TET3 using brain stereotaxic techniques to inject a Tet3 knockdown interference virus into the dorsal hippocampus of Pb, Hg, and Cd co-exposure offspring. We observed improved cognitive recognition after downregulation of the TET3 in Pb, Hg, and Cd co-exposure pups, mirroring the protective effects of methionine. In summary, our study identifies methionine as a promising dietary intervention to counteract Pb, Hg, and Cd neurotoxicity during pregnancy, mediated through the modulation of TET3.