Weight stigma, which involves negative judgments and discrimination based on body weight through experienced weight stigma (EWS) and internalized weight stigma (IWS), has been linked to adverse health outcomes. Following the association of weight stigma variables with GI diagnoses by Jansen et al. (2024), in this secondary analysis, self-esteem and depression are proposed to mediate this relationship as weight-related discrimination can diminish self-worth and exacerbate depressive symptoms, potentially impacting functional and structural gastrointestinal (GI) health. This study aims to examine the potential mediating roles of depression and self-esteem on the relationship between weight stigma (IWS and EWS) and GI health (probable irritable bowel syndrome (IBS) and other self-reported structural GI diagnoses). The study participants (N=400) aged 18+ were recruited through a Qualtrics research panel reflecting the BMI distribution of the United States population. Probable IBS diagnosis was determined by either meeting the Rome IV criteria or through self-report (N=65), and other GI diagnoses were determined by self-report (N=38). Separate simple mediation analyses examined whether depression and self-esteem mediated the relationship between weight stigma variables and the outcome variables of probable IBS diagnosis and other GI diagnoses, with demographic variables of gender, race, ethnicity, sexual orientation, and BMI as covariates for all analyses and other GI diagnoses included as a covariate for analyses examining probable IBS diagnosis. There was considerable evidence for significant mediation effects. Depression fully mediated the relationship between IWS and other GI diagnoses (indirect effect = 0.13, SE = 0.08, 95% CI [-0.04, 0.34]) and probable IBS diagnosis (indirect effect = 0.18, SE = 0.07, 95% CI [0.04, 0.34]), and fully mediated the relationship between EWS and probable IBS diagnosis (indirect effect = 0.11, SE = 0.04, 95% CI [0.04, 0.20]). Depression partially mediated the relationship between IWS and other GI diagnoses, and self-esteem partially mediated the relationships of IWS and EWS between both IBS and GI diagnoses (direct effects ps < .05). These findings highlight the importance of addressing psychological factors in managing weight stigma and its impact on GI health.