Environmental lead (Pb) exposure can induce dysbacteriosis, impair oral health, and is associated with the development of dental caries. However, the mechanism is unclear. The aim of this study was to explore the effects of Pb toxicity on oral antimicrobial activity in children in an e-waste area. Results showed higher blood Pb levels in e-waste-exposed group children, accompanied by decreased saliva SAG (salivary agglutinin) concentrations, increased peripheral WBC (white blood cell) counts and monocyte counts, and elevated peripheral monocyte percentage. LnPb (natural logarithmic transformation of blood Pb level) was negatively correlated with saliva SAG concentration, while positively correlated with peripheral monocyte percentage. Saliva SAG concentration played a complete mediating role in the correlation of LnPb to peripheral monocyte percentage. To our knowledge, this is the first study on the relationship of environmental Pb exposure and oral antimicrobial activity in children, showing that environmental Pb exposure may weaken oral antimicrobial activity through reducing saliva SAG concentration, which may raise the risk of oral dysbacteriosis and ultimately pathogen infection.