|Volume Regulated Anion Channels (VRACs) encoded by the LRRC8 gene family play critical roles in myriad cellular processes and might represent druggable targets. The dearth of pharmacological compounds available for studying VRAC physiology led us to perform a high-throughput screen (HTS) of 1,184 of FDA-approved drugs for novel VRAC modulators. We discovered the cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, Pranlukast, as a novel inhibitor of endogenous VRAC expressed in HEK293 cells. Pranlukast inhibits VRAC voltage-independently, reversibly, and dose-dependently with a maximal efficacy of only ~50%. The CysLT1R pathway has been implicated in activation of VRAC in other cell types, prompting us to test whether Pranlukast requires the CysLT1R for inhibition of VRAC. Quantitative PCR analysis demonstrated that CYSLTR1 mRNA is virtually undetectable in HEK293 cells. Furthermore, the CysLT1R agonist LTD4 had no effect on VRAC activity and failed to stimulate Gq-coupled receptor signaling. Heterologous expression of the CysLT1R reconstituted LTD4-CysLT1R-Gq-calcium signaling in HEK293 cells but had no effect on VRAC inhibition by Pranlukast. Additionally, we show the CysLT1R antagonist Zafirlukast inhibits VRAC with an IC50 of ~17 µM and does so with full efficacy. Finally, we also discovered zinc pyrithione, a compound commonly found in OTC antidandruff shampoo, activated endogenous VRAC expressed in HEK293 and HCT116 cells. Zinc pyrithione increased the rate of activation of swelling-activated VRAC currents, potentiated steady-state currents in a reversible manner, and activated currents in the absence of swelling via a reactive oxygen species dependent mechanism. Collectively, these studies provide clarifying insights into the putative role of leukotriene signaling in modulation of VRAC, identifies two new chemical scaffolds that can be used for development of more potent and specific VRAC inhibitors, and identifies a novel activator of VRAC.