Matrix metalloproteinases (MMPs) and tumor necrosis factor alpha (TNF‐α) play important and related roles in the pathogenesis of nerve injury. MMP‐dependent and TNF‐α‐dependent processes of neurodegeneration, such as blood‐nerve breakdown and immune cell recruitment, are characteristic of leprosy nerve damage. Our work has contributed to the understanding of the role of cytokines in the process, but the role of MMPs in the pathogenesis of neuritic leprosy has not been investigated. This study analyzed the changes in mRNA expression and immunodistribution of MMP‐2, MMP‐9, TNF‐α‐converting enzyme (TACE), TNF‐α in nerves of 27 pure neuritic leprosy (PNL) patients, both acid‐fast bacilli positive (AFB⁺) and acid‐fast bacilli negative (AFB⁻), and 8 non‐leprosy patients with control peripheral neuropathic conditions. MMP‐2, MMP‐9, and TNF‐α mRNA expression was significantly induced in the AFB⁻ relative to the AFB⁺ neuritic leprosy group and nonlepritic controls; TACE levels were also elevated in the AFB⁻ group, but this change was not statistically significant. Immunoreactive profiles for TNF‐α and MMPs demonstrated strong reactivity of myelinated axons, infiltrating macrophages, Schwann cells, endothelial cells, and perineurial cells in neuritic leprosy biopsies. This study provides the evidence of the involvement of MMPs in the pathogenesis of PNL neuropathy.