Background: Classical medial wedge (CMW) orthoses have been prescribed to treat overpronation foot pathologies in runners. The effects of a novel supination orthosis (NSO) on the surface electromyography (EMG) activity of the peroneus longus (PL) muscle during a complete cycle of running have yet to be tested. Purpose/Hypothesis: The purpose of this study was to compare the EMG activity of the PL in participants wearing CMW orthoses and NSOs versus neutral running shoes (NRS) during a full cycle of running gait. It was hypothesized that the PL muscle activity would be lower for the NSO compared with CMW or NRS. Study Design: Controlled laboratory study. Methods: Included were 31 healthy recreational runners of both sexes (14 male and 17 female; mean age, 38.58 ± 4.02 years) with a neutral Foot Posture Index and standard rearfoot-strike pattern. Participants ran on a treadmill at 9 km/h while wearing NSO (3-, 6-, and 9-mm thicknesses), CMW (3-, 6-, and 9-mm thicknesses), and NRS, for a total of 7 different conditions randomly selected, while the EMG signal activity of the PL was recorded for 30 seconds. Each trial was recorded 3 times, and the intraclass correlation coefficient (ICC) to test reliability of the measurements was calculated. The Wilcoxon pair to pair nonparametric test with Bonferroni correction was performed to analyze differences among the conditions. Results: The reliability of all assessments was almost perfect (ICC, >0.81). For both the CMW and NSO, regardless of thickness, the PL activity was statistically significantly lower compared with the NRS ( P < .05 for all). For all CMW thicknesses, the PL activity was lower compared with the respective NSO thicknesses, with the 3-mm thickness having the largest difference (CMW3mm, 18.63 ± 4.64 vs NSO3mm, 20.78 ± 4.99 mV; P < .001). Conclusion: Both CMW and NSO produced reduced EMG activity of the PL muscle; therefore, they can be prescribed to treat overpronation pathologies without associated PL strain concerns. In addition, the NSO saved the enhancement material placed on the medial-rear side of CMW, making it easier to wear sports shoes. Clinical Relevance: Knowing the safety of CMW and NSO will aid in understanding treatments for overpronation pathologies.