<b><i>Introduction:</i></b> The prevalence rates of obesity have increased in recent decades; despite leveling off in recent German studies among children and adolescents, obesity rates remain high. Psychosocial factors have an adverse impact on the maintenance of obesity. Hence, this study examined the mediating effects of mental health problems on the relation between the body mass index standard deviation score (BMI-SDS) and global health-related quality of life (HRQoL) among adolescent inpatients with obesity while controlling for gender and age-group. <b><i>Methods:</i></b> Three simple mediation analyses with gender and age-group as covariates were conducted for <i>n</i> = 313 adolescents with obesity (<i>n</i><sub>female</sub> = 193, 61.7%) aged 12–17 (M = 14.19, SD = 1.52; BMI-SDS: M = 2.67, SD = 0.52). The adolescents were asked to report their global HRQoL at admission, and their parents estimated the children’s mental health problems at home prior to inpatient rehabilitation. <b><i>Results:</i></b> Emotional, peer-related, and conduct problems mediated the unfavorable effects of BMI-SDS on global HRQoL, showing high, moderate, and small effect sizes, respectively (completely standardized indirect effect of emotional problems: β = −0.09, SE = 0.03, 95% B-CI = −0.15 to −0.04; conduct problems: β = −0.03, SE = 0.02, 9<i>5</i>% B-CI = −0.06 to −0.01; peer-related problems: β = −0.10, SE = 0.03, 95% B-CI = −0.16 to −0.05). <b><i>Conclusion:</i></b> Mental health problems may be one salient pathway through which BMI-SDS impairs global HRQoL among adolescents with obesity. Hence, inpatient rehabilitation programs for adolescents with obesity should increase their focus more on the development of psychosocial skills. Thus, the promotion of emotion regulation and social-emotional competencies is suggested.