Background <p>Colorectal cancer is a leading cause of cancer-related morbidity globally. Early detection through screening can markedly reduce mortality; however, participation remains suboptimal across diverse populations, including Iran. Understanding predictors of screening behaviour is essential to inform effective interventions. This study investigates predictors of colorectal cancer screening participation, framed by the Preventive Health Model (PHM) with health literacy as a key construct.</p> Methods <p>A cross-sectional survey was administered to employees aged 40 and older at a university. Participants completed validated instruments measuring PHM constructs and health literacy. Data were analysed with SPSS using multivariate regression to identify independent predictors of screening uptake.</p> Results <p>Higher levels of self-efficacy (<i>p</i> = 0.001, ß=0.44), perceived susceptibility (<i>p</i> = 0.002, ß=0.32), intention (<i>p</i> = 0.006, ß=0.27), and social support (<i>p</i> = 0.009, ß=0.22) were all significantly associated with participation in colorectal cancer screening, with self-efficacy being the strongest predictor. Conversely, there were no significant relationships found between cancer worries (<i>p</i> = 0.09, ß=-0.08), response efficacy (<i>p</i> = 0.40, ß=0.04), health literacy (<i>p</i> = 0.09, ß=0.08), and colorectal cancer screening.</p> Conclusions <p>Health literacy supports comprehension but self-efficacy and social support more strongly predict screening participation. Interventions should prioritize boosting self-efficacy and fostering supportive environments to enhance uptake.</p>