Background <p>Health literacy is a critical social determinant of health (SDH) that can influence the professional performance of healthcare workers. However, evidence from randomized controlled trials (RCTs) on the effectiveness of structured health literacy training on self-efficacy and occupational well-being among primary health workers is limited. This study aimed to evaluate the effectiveness of a multi-component educational intervention (integrating health literacy fundamentals, self-efficacy theory, communication skills, and stress management) on perceived self-efficacy and occupational well-being.</p> Methods <p>This RCT employed a pretest-posttest design with a control group. A total of 88 health workers were randomly allocated to either an intervention group (<i>n</i> = 44) or a control group (<i>n</i> = 44) using two-stage random sampling. The intervention group received an 8-session health literacy training program (60&#xa0;min per session, two sessions per week), while the control group received no training. Data were collected using the Ansari Self-Efficacy Questionnaire (20 items, three dimensions: perseverance, self-regulation, effort) and the Zheng Occupational Well-being Questionnaire (18 items, three dimensions: personal life well-being, work well-being, psychological well-being). Data were analyzed using repeated measures ANOVA and MANCOVA in SPSS-26.</p> Results <p>No significant differences were found between the two groups at baseline (<i>p</i> &gt; 0.05). MANCOVA results showed a significant effect of the intervention on the combined dependent variables (self-efficacy and occupational well-being) (<i>P</i> &lt; 0.001, η² = 0.247, power = 0.998). In the intervention group, mean self-efficacy scores increased from 75.40 to 82.00 (<i>P</i> = 0.001), and mean occupational well-being scores increased from 87.75 to 91.72 (<i>P</i> = 0.004), while no significant changes were observed in the control group. Additionally, a strong positive correlation was found between self-efficacy and occupational well-being in the post-test phase (<i>r</i> = 0.518, <i>P</i> &lt; 0.001).</p> Conclusion <p>A structured multi-component educational intervention significantly improves perceived self-efficacy and occupational well-being among health workers. Based on these findings, such training may be considered for integration into in-service education programs, particularly in similar primary healthcare settings. However, further research in larger and more diverse samples is needed before widespread policy recommendations can be made.</p> Clinical trial number <p>Not applicable.</p>