Objective: Obesity is associated with a range of negative psychological conditions that may also affect physiological health. Across two studies, we tested whether a range of psychological measures explain why obesity is prospectively associated with physiological dysregulation, measured via clinical indicators of cardiovascular, immune system, and metabolic function. Methods: We used comparable 4-year follow-up representative longitudinal data of UK and US older adults (≥ 50 years) from the English Longitudinal Study of Ageing (ELSA) (2008/2009–2012/2013) (Study 1; n= 6,250) and the Health and Retirement Study (HRS) (2008/2010–2012/2014) (Study 2; n=9,664). Fourteen and 21 psychological measures (e.g., depressive symptoms, life satisfaction, weight stigma, positive affect) were tested as candidate mediators in Studies 1 and 2, respectively. Results: Obesity predicted physiological dysregulation at follow-up across both studies. In Study 1, only weight stigma (measured between baseline and follow-up) explained 37% of the association between obesity and physiological dysregulation. In Study 2, only changes in weight stigma from baseline to follow-up (not baseline weight stigma) explained 13% of the effect of obesity on future physiological dysregulation. Mediation by weight stigma in both studies was partially attenuated when changes in body mass index (BMI) from baseline to follow-up were controlled for. No other psychological measures explained the association between obesity and physiological dysregulation in either study. Conclusion: The prospective association between obesity and physiological dysregulation was largely not explained by psychological factors. However, experiencing weight stigma is associated with increased weight gain and this process may explain obesity-related declines in physiological health.