Significance Calcium-activated chloride channels (CaCCs) serve important physiological functions, including modulation of signal processing of neurons in the central and peripheral nervous system. In this study, we uncover a previously underappreciated role for TMEM16A, an evolutionarily conserved CaCC, in regulating cytoplasmic chloride homeostasis and membrane remodeling events in nonexcitable epithelial tissues. TMEM16A-mediated intracellular chloride homeostasis can modulate the partitioning of membrane phosphoinositides and endocytic transport, providing a new mechanism that controls membrane dynamics, a key property of eukaryotic cell membranes important for numerous cellular processes in development and diseases.