Background: Pulmonary tuberculosis (PTB) remain one of the leading causes of morbidity, incapacity, and mortality around the globe. Effective TB control is hampered by the evolution of drug resistance to TB treatments. Objective: The study assessed the impact of nurse-led health education on factors affecting non-compliance to anti-tuberculosis drug regimens among pulmonary tuberculosis patients in referral hospitals, Delta state, Nigeria. Method: A quasi-experimental design involving intervention and control groups was employed, and a sample of 198 was drawn from the total population of 360 patients, using the multistage sampling technique. The study three-phased work, pre-intervention, intervention and post-intervention. A self-developed validated structured questionnaire and checklist developed by the researchers were used for data collection. The pre-post-test was administered to both the intervention and control groups while only the intervention group received health education intervention. Post-test data were collected from both groups one (1) month after the health education intervention groups. Findings were analysed using descriptive and inferential statistics. Inferential statistics were used for group comparisons and tested the impact of the intervention. Independent sample t-test and chi-square were used for group comparison at a 5% level of significance. Result: Baseline findings revealed that long duration of taking the drugs, discontinuance due to feeling of side effects and relief from ailment were identified as the most common factors affecting compliance to PTB drug regimen at the pre-intervention phase [long duration: con. (38.9%), int. (91.1%); side effects: con. (10.0%), int. (90.0%); feeling relief: con. (6.7%), int. (90.0%)] the post-intervention impact of the contributory factors to non-compliance was drastically reduced in the intervention than in the control group. Health education had a significant effect on compliance with the TB drug regimen. Conclusion: The study concluded that health education has a significant impact on factors affecting compliance. The study recommends that TB education should be adopted as part of the referral centres’ management policy.