Background: Adolescent cancer survivors constitute a clinically vulnerable population whose psychosocial adjustment following oncological treatment remains insufficiently characterized, particularly within Central and Eastern Europe. The present study aimed to evaluate health-related quality of life (HRQoL) and depressive symptomatology among Polish adolescent survivors, identify their psychological predictors, and determine age-related differences in these associations. Methods: A cross-sectional study was conducted among 165 survivors aged 11–18 years, recruited from four pediatric oncology centers. Participants completed the KIDSCREEN-10 (HRQoL) and the Children’s Depression Inventory-2™ (CDI-2™). Descriptive statistics, Spearman rank-order correlations, and multiple regression analyses were performed separately for younger (primary school) and older (secondary school) cohorts. Results: The findings demonstrated a pronounced polarization of HRQoL, with approximately one-third of participants (32.7%) scoring within the clinically low range. Depressive symptoms were prevalent, particularly in the domains of Negative Mood (M = 19.93) and Ineffectiveness (M = 15.45), while Negative Self-Esteem levels were comparatively low (M = 8.02). HRQoL correlated strongly and inversely with Interpersonal Problems (rs = −0.89, p < 0.001). Regression analyses indicated that Negative Self-Esteem (CDI-2D) was the strongest negative predictor of HRQoL in both age groups, whereas Ineffectiveness (CDI-2C) and Negative Mood (CDI-2A) emerged as significant positive predictors. Interpersonal Problems (CDI-2B) were predictive only in older adolescents, suggesting a developmental shift in determinants of well-being. Conclusions: Adolescent cancer survivors exhibit a distinctive psychological pattern characterized by pronounced emotional distress without pervasive self-devaluation. HRQoL appears highly polarized and primarily determined by self-esteem and interpersonal functioning. These findings underscore the necessity of developmentally tailored psychosocial interventions addressing self-worth, peer reintegration, and socio-economic stressors in survivorship care.