Purpose: this study aims to develop and test a model examining the causal relationship between self-efficacy, social support, fatigue, pain, functional status, and health-related quality of life (HRQL). Methods: A cross-sectional correlation study was conducted using a multi-stage sampling technique to recruit 256 individuals aged 20 to 59 with colorectal cancer (CRC) post-surgery from three hospitals in Northern Vietnam. The hypothesized model, based on Ferrans' HRQL conceptual model and literature review, was validated using structural equation modeling (SEM) and Mplus. Results: the model fit the data well, explaining 52% of the variance of HRQL. Self-efficacy emerged as the most influential factor directly impacting HRQL (beta = .494, p < .05) and also had negative indirect effects on HRQL through fatigue and pain (beta = -.271, p < .05). Social support had a positive direct (beta = .406, p < .001) and negative indirect effects on HRQL via fatigue and pain (beta = -.143, p < .05). Fatigue and pain had negative indirect effects on HRQL through functional status (beta = -.336, p < .05 and beta = -.219, p < .05, respectively). Functional status had a positive direct effect on HRQL (beta = .418, p < .001). Conclusions: The study's findings highlight the importance of improving self-efficacy, social support, and functional status, while reducing fatigue and pain to enhance HRQL among individuals with CRCpost-surgery. These insights can inform the development of targeted interventions to improve the well-being of this population.