Circulating adiponectin has some association with the risk of osteoporosis and cancers, but their causal relationships remains elusive. Mendelian randomization (MR) study was used to explore the causal roles of circulating adiponectin in osteoporosis and cancers by using genome-wide association studies (GWASs) associated with circulating adiponectin, osteoporosis and cancers. Fifteen single nucleotide polymorphisms (SNPs) were used as instrumental variables for circulating adiponectin. Genetic predisposition to high circulating adiponectin was strongly associated with low femoral neck bone mineral density (FN-BMD, beta-estimate:​ -0.015, 95% CI:​ −0.023 to −0.006, SE:​ 0.004, P-value = 0.001), low forearm BMD (FA-BMD, beta-estimate:​ -0.027, 95% CI:​ −0.050 to −0.004, SE:​ 0.012, P-value = 0.023) and increased risk of breast cancer (beta-estimate:​ 0.011, 95% CI:​ 0.001 to 0.022, SE:​ 0.005, P-value = 0.031). There was limited evidence of the associations between circulating adiponectin and other outcomes (i.e. lumbar spine BMD [LS-BMD], colorectal cancer, liver cancer, lung cancer, bone cancer and prostate cancer). This study provides robust evidence that high circulating adiponectin is causally associated with low FN-BMD, low FA-BMD and increased risk of breast cancer, which may provide new insight to prevent and treat osteoporosis and breast cancer.