Significance We previously demonstrated that induced pluripotent stem cell (iPSC)-derived cortical neurons from HSV-1 encephalitis patients with Toll-like receptor 3 (TLR3) pathway deficiencies are highly susceptible to HSV-1, due to impairment of cell autonomous TLR3-IFN immunity. In this study we present a protocol for efficient derivation/purification of trigeminal ganglion (TG) neurons from human iPSCs. The resulting TG neurons are of sensory identity and exhibit robust biological function. We also show that TG neurons and cortical neurons play distinct roles in host defense against HSV-1 in the central nervous system: unlike cortical neurons, TG neurons are vulnerable to HSV-1 because they require preemptive induction of TLR3-, IFN-α/β–mediated immunity. This is an important step to further our understanding of the HSV-1 encephalitis disease mechanism.