Adiponectin is an adipocyte hormone that is predominantly secreted by adipocytes, and has important roles in glucose and lipid homeostasis. Recent studies have shown that adiponectin is also involved in the regulation of many endocrine organs, such as the ovary, adrenal gland, and pituitary. However, its biological role in male testes is largely unexplored. The present findings demonstrate the presence of adeponectin receptors (adiponectin receptor 1 and adiponectin receptor 2) in TM3 cells derived from mouse Leydig cells. Proinflammatory cytokine treatment significantly downregulated mRNA and protein levels of adiponectin receptor 1 and adiponectin receptor 2. However, adiponectin pretreatment successfully inhibited the signaling pathway mediated by proinflammatory cytokines. At the molecular level, we provide compelling evidence that adeponectin achieves this by suppressing nuclear factor‐κB activation through promotion of AMP‐activated protein kinase phosphorylation. Thus, our data clearly indicate that adiponectin plays a protective role in Leydig cells through its anti‐inflammatory actions.