BackgroundNon-steroid anti-inflammatory drugs (NSAIDs) rank among the frequently prescribed medications for addressing pain and inflammation. Although they are powerful pain relievers, their side effects are indisputable. Serrapeptase, a serine protease, exhibits anti-inflammatory and anti-oedemic activity without the side effects of NSAIDs. We aim to assess the efficacy and safety of serrapeptase in the treatment of pain and edema in ankle sprains. MethodsIn a single-centre prospective comparative study, 76 patients aged 18–53 with Grade II ankle sprains were assigned to either a serrapeptase intervention group (n = 38) receiving 5 mg serrapeptase (two tablets, three times per day) for ten days, or a control group (n = 38) receiving 500 mg paracetamol (three times per day) for the same duration. Ankle joint edema was assessed using both Figure-of-Eight and water-displacement methods. Pain was assessed with Visual Analogue Scale (V.A.S.). Within-groups and between-groups analyses were performed in the 3rd and 10th day. ResultsBoth groups exhibited reduced edema and pain over time. Serrapeptase demonstrated a superior reduction in ankle joint edema on the third and tenth day compared to paracetamol, while pain management did not differ significantly. ConclusionSerrapeptase exhibited better efficacy than paracetamol in reducing ankle joint edema, highlighting its potential as an alternative treatment. Level of evidenceLevel II, prospective comparative trial without randomization.