Available safety evaluations regarding mesoporous silica nanoparticles (mSiNPs) are based on the assumption of a relatively high exposure concentration, which makes the findings less valuable in a realistic environment. In this study, we employed () as a model to assess the neuronal damage caused by mSiNPs at the predicted environmentally relevant concentrations. After nematodes were acute and prolonged exposed to mSiNPs at concentrations over 300 μg/L, locomotion degeneration, shrinking behavior, and abnormal foraging behavior were observed, which were associated with the deficits in the development of GABAergic neurons, including D-type and RME motor neurons. Furthermore, the oxidative stress evidenced by excessive ROS generation might contribute to the mechanism of mSiNPs damaging neurons. Although the neurotoxicity of mSiNPs was weaker than (nonmesoporous) SiNPs, it is still necessary for researchers to pay attention to the adverse effects caused by mSiNPs in the environmental animals, especially with the rapid increase in mSiNPs application. Considering the conserved property of GABAergic neurons during evolution, these findings will shed light on our understanding of the potential eco-risks of NPs to the nervous system of other animal models.