The immune system plays a vital role in brain development. The hepatitis B vaccine (HBV) is administered to more than 70% of neonates worldwide. Whether this neonatal vaccination affects brain development is unknown. Newborn C57BL/6 mice were injected intraperitoneally with HBV or phosphate-buffered saline. HBV induced impaired behavioral performances and hippocampal long-term potentiation at 8 weeks (w) of age without influence at 4 or 12w. At 6w, there was decreased neurogenesis, M1 microglial activation and a neurotoxic profile of neuroimmune molecule expression [increased tumor necrosis factor-α and reduced interferon (IFN)-γ, brain-derived neurotrophic factor and insulin-like growth factor-1] in the hippocampus of the HBV-vaccinated mice. In the serum, HBV induced significantly higher levels of interleukin (IL)-4, indicating a T helper (Th)-2 bias. Moreover, the serum IFN-γ/IL-4 ratio was positively correlated with the levels of neurotrophins and neurogenesis in the hippocampus at the individual level. These findings suggest that neonatal HBV vaccination of mice results in neurobehavioral impairments in early adulthood by inducing a proinflammatory and low neurotrophic milieu in the hippocampus, which follows the HBV-induced systemic Th2 bias.