The aim of study is to investigate the role of transient receptor potential cation channel subfamily V member 1 (TRPV1) on xerostomia-induced inflammatory response in vivo. Parotid, submandibular, and lingual gland were removed for xerostomia induction. The expression of inflammatory cytokines, TRPV1, NFkB, and MAPK in xerostomia was evaluated and compared in both TRPV1 wild and knockout mice. The level of interleukin-6 (IL-6) and IL-17, neutrophil/CD4 T-cell infiltration, phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N terminal kinase, TRPV1, and the localization of NFkB were elevated in xerostomia-induced TRPV1 wild-type mice. In contrast, inflammatory cytokines and MAPK were decreased in xerostomia-induced TRPV1 knockout mice. TRPV1 antagonist treatment also reduced tongue ulceration, neutrophil/CD4+ T-cell expression, IL-6, and IL-17 in TRPV1 wild-type mice. TRPV1 had a crucial role in modulating inflammation in xerostomia and targeting TRPV1 might be a promising therapeutic strategy for xerostomia. © 2019 Wiley Periodicals, Inc.