Study Design Randomized clinical trial. Objective To compare the effectiveness of manual therapy and exercise (MTEX) to a home exercise program (HEP) in the management of individuals with an inversion ankle sprain. Background An in-clinic exercise program has been found to yield similar outcomes as an HEP for individuals with an inversion ankle sprain. However, no studies have compared an MTEX approach to an HEP. Methods Patients with an inversion ankle sprain completed the Foot and Ankle Ability Measure (FAAM) activities of daily living subscale, the FAAM sports subscale, the Lower Extremity Functional Scale, and the numeric pain rating scale. Patients were randomly assigned to either an MTEX or an HEP treatment group. Outcomes were collected at baseline, 4 weeks, and 6 months. The primary aim (effects of treatment on pain and disability) was examined with a mixed-model analysis of variance. The hypothesis of interest was the 2-way interaction (group by time). Results Seventy-four patients (mean ± SD age, 35.1 ± 11.0 years; 48.6% female) were randomized into the MTEX group (n = 37) or the HEP group (n = 37). The overall group-by-time interaction for the mixed-model analysis of variance was statistically significant for the FAAM activities of daily living subscale (P<.001), FAAM sports subscale (P<.001), Lower Extremity Functional Scale (P<.001), and pain (P⩽.001). Improvements in all functional outcome measures and pain were significantly greater at both the 4-week and 6-month follow-up periods in favor of the MTEX group. Conclusion The results suggest that an MTEX approach is superior to an HEP in the treatment of inversion ankle sprains. Registered at clinicaltrials.gov (NCT00797368). Level of Evidence Therapy, level 1b-. J Orthop Sports Phys Ther 2013;43(7):443–455. Epub 29 April 2013. doi:10.2519/jospt.2013.4792