Post-traumatic injury pain is commonly treated with oral nonsteroidal anti-inflammatory drugs (NSAIDs). However, oral NSAIDs causes several adverse events, with topical formulations arising as an important alternative. Therefore, we aimed to evaluate the efficacy and safety of loxoprofen patch in the treatment of patients with post-traumatic pain. This phase III, randomized, double-blind, non-inferiority study enrolled Brazilian patients aged 18-65 years diagnosed with lower and upper limbs post-traumatic injury who were experiencing moderate or severe pain. Patients were assigned to active loxoprofen patch (LX-P) or to loxoprofen tablet (LX-T) and pain intensity was measured based on a Visual Analog Scale (VAS) score variation after seven days of treatment. Data on clinical symptoms, rescue medication use, and adverse events were also collected. VAS score variation was compared using a 10% non-inferiority margin. Two hundred and forty-two patients were randomly assigned to the LX-P (n=123) or to LX-T (n=119). The results showed a reduction in pain after seven days of treatment: -49.96 (n=118; SE 1.7) in the LX-P and -47.71 (n=117; SE 1.6) in the LX-T groups (difference of -2.25; 95% CI: -5.97 – 1.47; p=0.23). On the safety analysis, LX-T group presented twice as many patients with treatment-emergent adverse events as the LX-P group (30.8% and 14.2%, respectively). A sensitivity analysis demonstrated that rescue medication use has not affected the primary endpoint. This study showed that LX-P has a comparable efficacy to LX-T, but with a better safety profile, being a therapeutic option for the treatment of post-traumatic injury pain.