<p>Individuals with obesity frequently experience psychosocial challenges, such as weight stigma and weight-based rejection sensitivity (W-RS), which are linked to poorer health-related quality of life (HRQoL). However, the psychological mechanisms underlying these associations are not well understood. Grounded in cognitive appraisal theory, this study examined whether cognitive appraisal mediates the relationships between weight stigma, W-RS, and both physical and mental HRQoL. A cross-sectional design was used with 370 participants (M_age = 34.46 ± 11.58 years; 61% female), recruited through convenience sampling. Self-reported questionnaires, including the Stigmatizing Situations Inventory-Brief, Weight-Based Rejection Sensitivity Scale, Stress Appraisal Measure, and Short Form Health Survey, were used to collect data. Correlation analyses and structural equation modeling were conducted using SPSS 26 and AMOS 24. Findings revealed that experienced weight stigma was directly associated with lower physical and mental HRQoL. These relationships were partially mediated by cognitive appraisal (indirect effect: β = −0.09, <i>p</i> &lt; .05 for mental; β = −0.10, <i>p</i> &lt; .05 for physical HRQoL). W-RS was not directly associated with HRQoL, but this association was fully mediated by cognitive appraisal (indirect effect: β = −0.15, <i>p</i> &lt; .05 for mental HRQoL; β = −0.18, <i>p</i> &lt; .05 for physical HRQoL). These findings underscore the role of cognitive appraisal in shaping how individuals perceive and respond to weight-related social experiences. Interventions that promote more adaptive cognitive appraisal styles may help mitigate the adverse effects of stigma and W-RS, ultimately improving the mental and physical quality of life in this population.</p>