The zinc-dependent metalloprotease meprin α is predominantly expressed in the brush border membrane of proximal tubules in the kidney and enterocytes in the small intestine and colon. In normal tissue homeostasis meprin α performs key roles in inflammation, immunity, and extracellular matrix remodelling. The latter activity is furthermore important for driving aggressive metastasis in the context of certain cancers such as colorectal carcinoma. Accordingly, meprin α is the target of several drug discovery programs, however its structure is unknown. Meprin α is secreted into the extracellular space, whereupon it oligomerises to form giant supercoiled filamentous assemblies and is the largest extracellular protease identified to date (~6 MDa). Here, using cryo-electron microscopy, we determine the high-resolution structure of the zymogen and mature form of meprin α, as well as the structure of the active form in complex with a prototype small molecule inhibitor and native inhibitor (human fetuin-B). We resolve both the small molecule drug and an intricate intercalated inhibitory complex of meprin α/fetuin-B. Our data reveal that meprin α forms a giant, flexible, left-handed helical assembly of roughly 22 nm in width. Evolutionary analysis suggests these enormous filaments are biologically important, however their precise function remains enigmatic. Biophysical comparisons indicate that oligomerisation into supercoiled filaments improves the proteolytic and thermal stability, but does not impact substrate specificity or enzymatic activity of meprin α. Furthermore, structural comparisons with meprin β reveal unique features of the meprin α active site and helical assembly more broadly with implications for improving small molecule inhibitors. We hypothesise that the filamentous form of meprin α regulates the ECM remodelling activity by sequestering proteolysis to a localised context thereby maintaining correct tissue homeostasis.