Background: Acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy. To improve long-term health-related quality of life (HRQOL) in adult survivors of childhood ALL, more longitudinal studies are needed to assess outcomes and risk factors throughout treatment and survivorship. The aim of this study was to examine the long-term changes in HRQOL, self-efficacy, and social support among adult survivors of childhood ALL and to explore the temporal relationship between HRQOL, self-efficacy, and social support. Procedure: The study includes 148 adult childhood ALL survivors who responded to a questionnaire assessing HRQOL (SF36), self-efficacy (General Self-Efficacy Scale, GSE), and quantitative and qualitative social support (AVSI and AVAT in SS13) in 2012 and 2021. Changes in the HRQOL, GSE, and social support were calculated using paired t-tests. Bayesian path models were specified, and separate models were estimated for each relationship between GSE and AVSI, and AVAT and HRQOL. Cross-sectional associations, autoregressive effects within constructs over time, and cross-lagged effects between two variables over time were specified within each model. Results: The mean of six of the eight HRQOL dimensions, as well as quantitative and qualitative social support, deteriorated during the 9-year follow-up. Self-efficacy was unchanged. Temporal positive relationships were found between baseline GSE and the HRQOL dimension of social functioning, as well as between social support and the HRQOL dimensions of physical functioning, vitality, and mental health at follow-up. Conclusion: The findings highlight the importance of self-efficacy and social support as potential buffering factors for HRQOL in adult survivors of childhood ALL over time. © 2025 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.