Disturbances in endoplasmic reticulum (ER) Ca²⁺ homeostasis have been associated with many diseases including loss of salivary glands. Although significant progress has been accomplished which led to the increase in our understanding of the cellular responses to ER stress, the factors/ion channels that could inhibit ER stress are not yet identified. Here, we show that TRPC1 (transient receptor potential canonical 1) is involved in regulating Ca²⁺ homeostasis and loss of TRPC1 decreased ER Ca²⁺ levels, inhibited the unfolded protein response (UPR), that induced loss of salivary gland cells. We provide further evidence that ER stress‐inducing agents (Tunicamycin [Tu] and Brefeldin A [BFA]) disrupt Ca²⁺ homeostasis by directly inhibiting TRPC1‐mediated Ca²⁺ entry, which led to ER stress in salivary gland cells. Moreover, induction of ER stress lead to an increase in C/EBP homologous protein (CHOP) expression, which decreased TRPC1 expression and subsequently attenuated autophagy along with increased apoptosis. Importantly, TRPC1^−/− mice showed increased ER stress, increased immune cell infiltration, loss of Ca²⁺ homeostasis, decreased saliva secretion, and decreased salivary gland survival. Finally, restoration of TRPC1 not only maintained Ca²⁺ homeostasis but also inhibited ER stress that induced cell survival. Overall these results suggest a significant role of TRPC1 Ca²⁺ channels in ER stress and homeostatic function/survival of salivary gland cells.