The aim of this study was to examine the contribution of individual (positive reappraisal) and family factors (parenting satisfaction, couple relationship quality, and family life difficulty) to the psychological well-being (PWB) of parents of children/adolescents diagnosed with cancer. This cross-sectional study was conducted at two pediatric oncology wards in Portugal. Two-hundred and five parents of pediatric patients with cancer completed self-report questionnaires assessing the use of positive reappraisal as a coping strategy, parenting satisfaction, relationship quality, family life difficulty, and PWB. Sociodemographic and clinical data were also assessed. Standard multiple regression analysis showed a significant contribution of both individual- and family-level factors to parents' PWB. Specifically, the use of positive reappraisal as a coping strategy, parenting satisfaction, and relationship quality were associated with higher PWB; conversely, family life difficulty was linked to lower PWB. Sociodemographic (child's age and family's socioeconomic status) and clinical variables (time since diagnosis and treatment status) were not associated with PWB. The present study identified potential resources for parents' adaptation to this stressful situation, contributing with insightful conclusions for both research and clinical practice. Screening and addressing both individual- and family-level aspects may be crucial to foster parents' well-being when a child is diagnosed with cancer.