Sleep duration suggests some association with osteoporosis and cardiometabolic diseases, but it is unknown if these associations are causal or confounded. In this two-sample Mendelian randomization (MR) study, we included the largest genome-wide association studies (GWASs) associated with sleep duration and the outcome measures of osteoporosis and cardiometabolic diseases. Finally, 25 single nucleotide polymorphisms (SNPs) associated with short sleep duration and 7 SNPs associated with long sleep duration obtained the genome-wide significance (P < 5 × 10-8) and were used as instrumental variables. Genetic predisposition to short sleep duration was strongly associated with increased risk of coronary artery disease (beta-estimate: 0.199, 95% confidence interval CI: 0.081 to 0.317, standard error SE:0.060, P value = 0.001) and heart failure (beta-estimate: 0.145, 95% CI: 0.025 to 0.264, SE:0.061, P value = 0.017), which were both confirmed by the sensitivity analyses. Both short and long sleep duration may reduce the estimated bone mineral density (eBMD, beta-estimate: -0.086, 95% CI: -0.141 to -0.031, SE:0.028, P value = 0.002 for short sleep duration; beta-estimate: -0.080, 95% CI: -0.120 to -0.041, SE:0.020, P value < 0.0001 for long sleep duration). There was limited evidence of associations between sleep duration and fracture, type 2 diabetes, atrial fibrillation, fasting glucose, fasting insulin, or HbA1c. This study provides robust evidence that short sleep duration is causally associated with high risk of coronary artery disease and heart failure and suggests that short sleep duration should be avoided to prevent these two cardiovascular diseases. Short and long sleep duration show some MR association with reduced eBMD, which indicates that both short and long sleep duration may be prevented to reduce the incidence of osteoporosis.