Objectives <p>To determine whether handgrip strength is associated with the incidence of age-related macular degeneration.</p> Methods <p>A prospective cohort study of over 500 thousand UK Biobank participants aged 40–69 years. Individuals ≥ 50 years and without age-related macular degeneration at baseline were included. Exposure was the handgrip strength measured by dynamometer. Primary outcome was the incidence of age-related macular degeneration during 13 years of follow-up. Cox proportional-hazard models were fitted to estimate the risk effect for handgrip strength on age-related macular degeneration, and stratified for sociodemographic and lifestyle factors. Mediation models were regressed to explore underlying mechanisms driven by inflammatory and erythrocyte-related biomarkers.</p> Results <p>382174 eligible participants in the UK Biobank were included. After 4680431 person-year, 7987 individuals (2.09%) developed age-related macular degeneration. Individuals in the lowest quintile of handgrip strength had higher risk of age-related macular degeneration incidence (Hazard Ratio, 1.25; 95% CI, 1.16–1.35) compared with those in the highest quintile. Per 5&#xa0;kg decrement in handgrip strength was associated with increased risk of age-related macular degeneration incidence (Hazard Ratio, 1.06; 95% CI, 1.04–1.08) with similar trend among all subgroups except for sex. Specific inflammatory and erythrocyte-related biomarkers partially (37.5%) mediated the incidence of age-related macular degeneration as substantial biological mechanisms following handgrip strength decrease.</p> Conclusions <p>Our findings suggest that handgrip strength is associated with the incidence of age-related macular degeneration under the mediation of systemic proinflammatory factors. The current study holds an outlook for improved visual health over the evaluation and intervention of muscle strength in old-age population.</p>