Obesity-induced chronic low-grade inflammation and thus causes various metabolic diseases, such as insulin resistance and non-alcoholic fatty liver disease (NAFLD). Patchouli alcohol (PA), an active component extracted from patchouli, displayed anti-inflammatory effects on different cell types. However, the impact of PA on skeletal muscle insulin signaling and hepatic lipid metabolism remains unclear. This study aimed to investigate whether PA would affect insulin signaling impairment in myocytes and lipid metabolism in hepatocytes. Treatment with PA ameliorated palmitate-induced inflammation and aggravation of insulin signaling in C2C12 myocytes and lipid accumulation in HepG2 hepatocytes. Treatment of C2C12 myocytes and HepG2 cells with PA augmented AMP-activated protein kinase (AMPK) phosphorylation and Sirtuin 1 (SIRT1) expression in a dose-dependent manner. siRNA-mediated suppression of AMPK or SIRT1 mitigated the effects of PA on palmitate-induced inflammation and insulin resistance in C2C12 myocytes and lipid accumulation in HepG2 cells. Animal experiments demonstrated that PA administration increased AMPK phosphorylation and SIRT1 expression, and ameliorated inflammation, thereby attenuating skeletal muscle insulin resistance and hepatic steatosis in high-fat diet-fed mice. These results denote that PA alleviates skeletal muscle insulin resistance and hepatic steatosis through AMPK/SIRT1-dependent signaling. This study might provide a novel therapeutic approach for treating obesity-related insulin resistance and NAFLD.