Objectives To explore the utility of high-resolution ultrasonography (HRUS) in leprosy by assessing changes in peripheral nerves. Methods This study follows the Preferred Reporting Item for Systematic Review and Meta-analysis (PRISMA). Relevant studies up to 1 July 2024 were systematically searched using three databases, and the quality of the included studies was further assessed using the Newcastle-Ottawa Scale. Results The results consistently indicated that leprosy patients exhibited significant nerve thickening across various nerves, particularly the ulnar, median, and peroneal nerves with high sensitivity and specificity. Notably, HRUS also demonstrated its ability to detect subclinical nerve involvement in leprosy patients’ household contacts (HHC), suggesting its potential utility in early screening efforts. Conclusion HRUS emerges as a promising diagnostic tool for leprosy, offering enhanced objectivity and superior sensitivity and specificity compared to current diagnostic tools by detecting nerve involvement. This method is effective not only in diagnosing symptomatic patients but also in identifying nerve abnormalities in HHC and individuals without visible skin manifestations. © The author(s).