Fibroblast growth factor 21 (FGF21) is a human metabolic hormone that is being pursued in early stage clinical trials as pharmacological target to treat a range of metabolic diseases. In animal models, increased FGF21 signalling has been shown to have beneficial effects on cardiometabolic outcomes, Alzheimer’s disease risk and lifespan. However, studies investigating the effect of FGF21 signalling on these clinical outcomes in humans have been inconclusive. In this study, a genetic variant associated with higher circulating FGF21 levels was leveraged to investigate its clinical effects in humans. Higher genetically proxied circulating FGF21 levels were associated favourably with lipid levels, blood pressure traits, waist-to-hip ratio, chronic inflammation, cardiovascular outcomes, Alzheimer’s disease risk and lifespan. These findings may be used to anticipate the effects of pharmacologically increasing FGF21 signalling and inform the design of further clinical trials.