Posttraumatic stress symptoms (PTSS) are associated with serious impairments in psychological, social, and academic functioning in youth. The aim of this study was to investigate whether changes in posttraumatic cognitions mediate treatment effects. Participants were multitraumatized youth (N = 156, mean age = 15.1 years, range = 10–18; 79.5% girls) randomly assigned to receive trauma-focused cognitive–behavioral therapy (TF-CBT) or treatment-as-usual (TAU). Mixed-effects models were applied to investigate the impact of treatment conditions on posttraumatic cognitions. Mediation analyses were applied to examine whether changes in posttraumatic cognitions mediated the relationship between treatment conditions and outcome in posttraumatic stress symptoms, depressive symptoms, and general mental health. Participants receiving TF-CBT reported significantly lower levels of negative posttraumatic cognitions at the end of treatment compared to participants in TAU. Change in posttraumatic cognitions mediated the treatment effect difference found for PTSS. When the overall change in cognition was divided into early and late changes, it was only the late change that significantly mediated the PTSS treatment effect. A mediation effect of posttraumatic cognitions was also found for the treatment effect difference in depressive symptoms and in general mental health symptoms. Traumatized youth report having many negative posttraumatic cognitions and changes in negative cognitions plays a key role for treatment outcome.