Background: Quality of life (QoL) increasingly is being assessed in pediatric patients with cancer. However, only a few studies focused on QoL predictors during and after treatment for pediatric patients with cancer. Objective: The aims of this study were to (1) assess differences of QoL, distress behavior, and fatigue among children and adolescents; (2) examine the relationship of distress behaviors, fatigue, and a variety of demographic factors to QoL; and (3) identify QoL predictors. Methods: A cross-sectional descriptive study involving 150 participants treated between 2012 and 2014 was conducted. All participants were given a diagnosis of cancer, ranged in age from 7 to 18 years, and had no developmental delay or mental illness. Three instruments including Pediatric Quality of Life, Distress Behaviors, and Multidimensional Fatigue Scale were administered. Results: Adolescents aged 16 to 18 years reported lower school functioning and experienced more general and sleep/rest fatigue. Fatigue and distress behaviors were associated with a poorer QoL. Diagnosis at a younger age, greater time since diagnosis, and family structure were associated with a better QoL. General fatigue, relationship distress, family structure, and time since diagnosis were significant predictors of QoL, accounting for 64% of the total variance. Conclusions: Factors associated with a poorer QoL included fatigue, distress behaviors, and diagnosis at an older age. Less general fatigue and relationship distress, greater time since diagnosis, and living in nuclear family predicted a better QoL. Implications for Practice: Routinely evaluating fatigue and school functioning in pediatric patients with cancer is warranted, as well as developing educational programs to enhance the management of fatigue and relationship issues, especially for those who were given a diagnosis recently or for late adolescents.