Abstract Background Weight bias is widespread and has numerous harmful consequences. The internalization of weight bias has been associated with significant psychological impairment. Other forms of discrimination, such as racial and anti-gay bias, have been shown to be associated with physical health impairment. However, research has not yet examined whether internalized weight bias is associated with physical as well as psychological impairment in health-related quality of life. Methods Participants included 120 treatment-seeking overweight and obese adults (mean body mass index = 35.09; mean age = 48.31; 68% female; 59% mixed or Asian ethnicity). Participants were administered measures of internalized weight bias and physical and mental health-related quality of life, and they were assessed for the presence of chronic medical conditions, use of prescription and non-prescription medications, and current exercise. Results Internalized weight bias was significantly correlated with health impairment in both physical (r = −.25) and mental (r = −.48) domains. In multivariate analyses controlling for body mass index, age, and other physical health indicators, internalized weight bias significantly and independently predicted impairment in both physical (β = −.31) and mental (β = −.47) health. Conclusions Internalized weight bias was associated with greater impairment in both the physical and mental domains of health-related quality of life. Internalized weight bias also contributed significantly to the variance in physical and mental health impairment over and above the contributions of BMI, age, and medical comorbidity. Consistent with the association between prejudice and physical health in other minority groups, these findings suggest a link between the effects of internalized weight-based discrimination and physical health. Research is needed on strategies to prevent weight bias and its internalization on both a societal and individual level.