BACKGROUND: This systematic review examined the evidence on effectiveness and acceptability of cognitive behavioral therapy (CBT) interventions in improving quality of life (QoL) and psychological well-being of unaccompanied minors (UM). METHODS: PubMed, Scopus, Embase, ProQuest, PsycInfo, PsycArticles, and Open Dissertations databases were used to identify quantitative and qualitative studies. The Effective Public Health Practice Project (EPHPP) and Critical Appraisal Skills Programme (CASP) tools were used for quality assessment. Narrative synthesis and qualitative research synthesis were carried out to collate the findings. RESULTS: 18 studies were included. Two studies examined QoL, and five studies examined acceptability of interventions. Most quantitative studies (n = 10) were appraised as methodologically weak. Trauma-Focused CBT appears to have the most evidence demonstrating effectiveness in ameliorating symptoms of post-traumatic stress disorder, depression, and anxiety. Promising findings (i.e., increased mindfulness and psychological flexibility) were observed for third wave interventions but further replication is required. CONCLUSIONS: The literature is tainted by under-powered studies, lacking blinding, and follow-up assessments. Female UM remain largely underrepresented. This review calls for a drastic augmentation of high quality quantitative and qualitative research focusing on augmenting QoL and examining acceptability rather than merely aiming for psychological symptom reduction in UM to enhance overall well-being and functionality. The research protocol was registered in PROSPERO (registration number: CRD42021293881).