Living with an inflammatory bowel disease (IBD), while also navigating the demands of adolescence, may present a challenge for the quality of life (QoL) of adolescents. The current study examined the direct and indirect associations of the stressor (illness severity), cognitive appraisal (illness perception), personal (self-efficacy, positive affect, social support) and family coping resources (economic situation, family functioning) with adolescents’ QoL. This cross-sectional study was conducted in Israel. Participants were 74 adolescents (44 boys, 30 girls; aged 11–18 years old) living with IBD, who completed a self-report questionnaire during a clinic follow-up visit. Illness severity was not directly associated with QoL, and no mediating effects through illness perception or coping resources were found; however, social support moderated the association between illness severity and QoL. Additionally, illness perception had the highest direct contribution to QoL: adolescents who perceived their illness as a threat showed poorer QoL. This association was also moderated by social support. Social workers in multidisciplinary healthcare teams may contribute to the improvement of QoL among adolescents with IBD by conducting regular QoL screenings, encouraging adolescents to re-frame their perceptions of their illness, and fostering the receipt of social support using individual or child-parent education sessions and CBT interventions.