© 2020 Elsevier Inc.Background: This study aimed to compare the analgesic efficacy of topical capsaicin and topical piroxicam in acute musculoskeletal injuries. Methods: This is a prospective, randomized, controlled, double-blinded study. The data for the 67 patients in the piroxicam group and the 69 in the capsaicin group were examined. The initial visual analog scale (VAS) scores were compared with the 60th and 120th minute as well as the 24th and 72nd hour values. Differences between the VAS scores, clinical effectiveness of the treatment and side effects were evaluated. Results: In the capsaicin group, the mean difference in the delta VAS scores was significantly higher at each measurement time. The mean of the percentage of reduction in the VAS scores of the topical capsaicin group was significantly higher than that in the topical piroxicam group. The highest difference in terms of both outcomes was determined at the 72nd hour VAS change. Mean differences were 1.53 (95% CI: 0.85–2.221) and 19.7 (95% CI: 12.4–27.2) respectively (p < 0.001). In the capsaicin group, the clinical effect of the treatment was found significantly higher (p < 0.01). The difference between the clinical effectiveness of the groups regarding the treatment outcomes was also statistically significant (p < 0.001). There was no significant difference between the patient groups regarding the presence of side effects. Conclusion: Topical capsaicin can be used as an alternative to topical piroxicam initially and at follow-up in patients presenting to the emergency department with acute pain as there were no observable differences in side-effects between the two groups.