ObjectiveLiving a purposeful life is associated with better mental and physical health, including longevity. Accumulating evidence shows that these associations might be explained by the association between life purpose and regulation of physiological systems involved in the stress response. The aim of this study was to investigate the prospective associations between life purpose and allostatic load over a 10-year period. MethodsAnalyses were conducted using data from the Midlife in the United States (MIDUS) survey. Assessment of life purpose, psychological covariates and demographics were obtained at baseline, while biomarkers of allostatic load were assessed at the 10-year follow-up. ResultsWe found that greater life purpose predicted lower levels of allostatic load at follow-up, even when controlling for other aspects of psychological well-being potentially associated with allostatic load. Further, life purpose was also a strong predictor of individual differences in self-health locus of control—i.e., beliefs about how much influence individuals can exert on their own health—which, in turn, partially mediated the association between purpose and allostatic load. Although life purpose was also negatively linked to other-health locus of control—i.e., the extent to which individuals believe their health is controlled by others/chance—this association did not mediate the impact of life purpose on allostatic load. ConclusionThe current study provides the first empirical evidence for the long-term physiological correlates of life purpose and supports the hypothesis that self-health locus of control acts as one proximal psychological mechanism through which life purpose may be linked to positive biological outcomes.