Abstract Background This study aimed to assess the effectiveness of nurse-led interventions in managing leprosy due to a shortage of dermatologists and other healthcare professionals. Methods A total of 100 leprosy patients were divided into experimental (n=50) and control groups (n=50). The intervention included face-to-face counseling by a trained nurse, motivational videos and exercise demonstrations. The control group received standard care. The primary outcome of interest was treatment adherence (Adherence to Refills and Medications Scale); other assessed outcomes included changes in perceived stigma (Stigma Assessment and Reduction of Impact scale), depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder seven-item) and quality of life (WHO QOL–BREF Scale) from baseline to week 8. Results The intervention group had better treatment adherence (p<0.001). At baseline, moderately severe and severe depression prevalence was 18% and 28%, respectively, and anxiety was 25%, with no intergroup differences. Anxiety significantly decreased in the intervention group (p<0.001), but depression remained similar (p=0.291). Perceived stigma improved notably, especially in disclosure of concern (p<0.001), internal stigma (p<0.001) and anticipated stigma (p<0.001). Quality of life scores improved in the intervention group vs controls. Conclusion Nurse-led interventions effectively enhanced quality of life and treatment adherence and reduced anxiety, depression and perceived stigma among leprosy patients. The study recommends strengthening the capacity of nurses for active involvement in leprosy care.