羟甲基戊二酸单酰辅酶A还原酶（英语：hydroxymethylglutaryl-CoA reductase，EC 1.1.1.88）简称“HMG-CoA还原酶”，是一种以NAD或NADP为受体、作用于供体CH-OH基团上的氧化还原酶。这种酶能催化以下酶促反应：

HMG-CoA还原酶是产生胆固醇等类异戊二烯化合物的甲羟戊酸代谢途径中的限速酶。一般来说，在哺乳动物细胞中HMG-CoA还原酶受到由低密度脂蛋白受体内化及降解低密度脂蛋白产生的胆固醇及胆固醇的氧化衍生物的抑制。低密度脂蛋白是动脉粥样硬化的一个决定性因素，这种酶的竞争性抑制剂能诱导肝脏低密度脂蛋白受体的表达，使细胞质基质内低密度脂蛋白的代谢增强、浓度降低。因此，HMG-CoA还原酶成为被统称为“羟甲基戊二酸单酰辅酶A还原酶抑制剂”的一类被广泛使用的降胆固醇药的作用靶点。HMG-CoA被锚定在内质网膜上，且长期以来被认为拥有7个跨膜结构域，而其活性位点则位于蛋白质C端结构域中。但后来的研究表明HMG-CoA还原酶其实拥有8个跨膜结构域。

HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, officially abbreviated HMGCR) is the rate-controlling enzyme (NADH-dependent, EC1.1.1.88; NADPH-dependent, EC1.1.1.34) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor as well as oxidized species of cholesterol. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. This enzyme is thus the target of the widely available cholesterol-lowering drugs known collectively as the statins.