Circulating adiponectin shows some relationships with the occurrence of cardiometabolic diseases and osteoporotic fracture, but little is known about their causal associations. This two-sample Mendelian randomization (MR) study aims to explore the causal roles of circulating adiponectin in cardiometabolic diseases and osteoporotic fracture. We used 15 single nucleotide polymorphisms associated with circulating adiponectin as the instrumental variables. Inverse variance weighted, weighted median and MR-Egger regression methods were applied to study the causal associations. The results found that high circulating adiponectin was causally associated with reduced risk of type 2 diabetes (beta-estimate: -0.030, 95% CI: -0.048 to -0.011, SE: 0.009, P-value = 0.002) and may be the risk factor of coronary artery disease (beta-estimate: 0.012, 95% CI: 0.001 to 0.023, SE: 0.006, P-value = 0.030). No causal associations were seen between circulating adiponectin and other outcomes including heart failure, atrial fibrillation, cerebral ischemia, intracerebral hemorrhage or osteoporotic fracture. This study found the potential causal roles of high circulating adiponectin in reduced risk of type 2 diabetes and increased risk of coronary artery disease, which may help prevent and treat these two diseases.