The TMEM16A Ca²⁺-gated Cl^– channel couples intracellular Ca²⁺ handling with cell electrical activity in contractile vascular cells. The channel is a potential therapeutic target for diseases of impaired (micro)vascular blood flow, including cerebral. In the brain, increased neuronal activity is coupled with a rise in regional metabolic activity which leads to a concomitant increase in cerebral blood flow (CBF). Contractile pericytes, cells that surround capillaries, are important determinants of CBF by controlling the diameter of the capillary and microvascular resistance to blood flow. In ischaemia, pericytes contract and then die in rigor, hindering CBF. Here we show that TMEM16A is expressed in pericytes and constitutes a depolarising force in response to a rise in intracellular Ca²⁺ or ischaemia. We perform a systematic analysis of the selectivity and potency of several structurally unrelated synthetic modulators of the TMEM16A channel, including a range of test compounds, the FDA approved drug niclosamide, and a recently identified activator, termed PAM_16A in this study. Selective pharmacological inhibition or activation of TMEM16A, respectively reduced or increased pericyte Ca²⁺ rise and capillary constriction in response to GqPCR agonists, with no effect on the electrical activity of cortical neurons. Exposure of cortical slices to oxygen-glucose deprivation (OGD), to simulate ischaemia, led to pronounced pericyte death. This was reduced or further enhanced by pharmacological inhibition or activation of the TMEM16A channel, respectively. In a rodent stroke model, TMEM16A inhibition reduced the ischaemia-evoked Ca²⁺ rise, capillary constriction, and pericyte death. These pharmacological agents similarly modulated the tone of isolated rat aorta and mesenteric arteries, which also express the TMEM16A channel. In summary, capillary diameter, as well as the tone of a range of artery types, can be finely controlled with TMEM16A modulators. This highlights TMEM16A as a possible target in a range of disorders involving impaired vascular tone including stroke, vascular dementia and hypertension.