Objective Little is known about self-concept in adolescents with physical-mental comorbidity. This study investigated whether physical-mental comorbidity was associated with self-concept in adolescents and examined if adolescent age or sex moderated the association between physical-mental comorbidity and self-concept. Methods Study data were obtained from the Multimorbidity in Youth across the Life-course (MY LIFE), an ongoing Canadian study of adolescents with chronic physical illness who were recruited from outpatient clinics at a pediatric hospital. A total of 116 adolescents aged ≥ 10 years provided self-reports on key measures. Results Adolescents with comorbidity (n = 48) had lower self-concept scores on the Self-Determination Questionnaire (SDQ; d = 0.62) and Self-Perception Profile for Children (SPPC; d = 0.53) vs. adolescents without comorbidity (n = 68). An age × comorbidity status interaction was found and age-stratified models were computed to investigate this moderating effect of age. Amongst older adolescents, comorbidity was associated with lower SDQ (B = -2.55, p < .001), but this association was not found among younger adolescents (B = -0.29, p = .680). A similar effect was found for SPPC among older (B = -0.48, p = .001) and younger adolescents (B = 0.03, p = .842). Adolescent sex was not found to be a moderator. Conclusions Physical-mental comorbidity in adolescence was associated with lower self-concept and this association was moderated by age—differences between adolescents with vs. without comorbidity were greater for older adolescents and were clinically relevant. Opportunities to support positive self-perceptions for adolescents with comorbidity are warranted, especially when planning the transition from pediatric to adult health services.