Abstract The present study examined the cross-sectional and longitudinal associations between the five major personality traits and fatigue. Participants were adults aged 16–104 years old (N > 40,000 at baseline) from the Health and Retirement Study, the National Social Life, Health, and Aging Project, the Wisconsin Longitudinal Study graduate and sibling samples, the National Health and Aging Trends Survey, the Longitudinal Internet Studies for the Social Sciences and the English Longitudinal Study of Ageing. Personality traits, fatigue, demographic factors, and other covariates were assessed at baseline, and fatigue was assessed again 5–20 years later. Across all samples, higher neuroticism was related to a higher risk of concurrent (meta-analytic OR = 1.73, 95% CI 1.62–1.86) and incident (OR = 1.38, 95% CI 1.29–1.48) fatigue. Higher extraversion, openness, agreeableness, and conscientiousness were associated with a lower likelihood of concurrent (meta-analytic OR range 0.67–0.86) and incident (meta-analytic OR range 0.80–0.92) fatigue. Self-rated health and physical inactivity partially accounted for these associations. There was little evidence that age or gender moderated these associations. This study provides consistent evidence that personality is related to fatigue. Higher neuroticism and lower extraversion, openness, agreeableness, and conscientiousness are risk factors for fatigue.