Here we show that in a mouse dry eye model, the ocular (over)activation of transient receptor potential vanilloid 1 (TRPV1) channels in response to tear deficiency and tissue damage promotes neuroinflammatory gene expression and macrophage reactivity in the trigeminal ganglion, where the cornea-innervating sensory neurons are located. Here, TRPV1 is linked to Keratoconjunctivitis sicca.