Objective The association of obesity with a large range of physical conditions and numerous psychiatric disorders has been extensively studied. Our study sought the extent to which physical conditions or psychiatric disorders associated with obesity mediate the association of obesity with unemployment or disability. Method Using data from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III, 2012-2013), we estimated the prevalence of unemployment as a function of obesity taking into account these comorbidities. Data on self-reported height and weight were available for 35,725 respondents. Clinician-diagnosed physical conditions were self-reported and lifetime psychiatric disorders were assessed with a semi-structured interview. Results The adjusted prevalence of obesity was 30.4%. Participants with obesity were more likely than participants without obesity to report at least one of the 31 assessed physical conditions (64.46% vs 46.87%; p<0.001). Participants with obesity were more likely to report at least one of the 24 assessed psychiatric diagnoses than respondents without obesity (60.57 vs 56.75%; p<0.001). The rates of unemployment were higher in participants with obesity than in those without obesity (15.75% vs 11.26%; p<0.001). Similarly, participants with obesity reported higher rates of disability than those without obesity. While the number of physical conditions and psychiatric disorders partly explains this association, obesity remained significantly associated with unemployment and greater disability when controlling for the number of physical conditions and psychiatric disorders. Conclusion Obesity is associated with high rates of unemployment and with high disability. This is not explained solely by the high rate of physical conditions and psychiatric disorders associated with obesity.