Objective: To investigate the efficacy of a single intra-articular injection of high molecular weight hyaluronic acid (HMW-HA) for treating isolated medial osteochondral lesions (OCLs) of the talus following arthroscopic microfracture. Methods: A total of 39 patients, treated between 2014–2017 for medial OCLs of the talus, were enrolled in the study. Patients were split into two groups: group 1, consisting of 18 patients who received a single of 4 ml of HMW-HA (22 mg/ml) injection following microfracture; and group 2, consisting of 21 patients who underwent microfracture but did not receive an injection. Functional and clinical outcomes were assessed at baseline, 6 months, and at a final follow-up using a visual analogue scale (VAS) and the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale (AOFAS). Results: The mean AOFAS score increased in groups 1 and 2, from 45.61±14.71 to 95.11±5.02 (p=0.0001) and 41.81±13.83 to 90.29±7.43 (p=0.0001), respectively. Similarly, the mean VAS score decreased in groups 1 and 2 from 8.72±1.23 to 2.11±1.45 (p=0.0001) and 9.05±0.80 to 3.67±2.22 (p=0.0001), respectively. In addition, the mean AOFAS score in group 1 was higher than in group 2 (p=0.025) at the final follow-up, and the mean VAS score in group 1 was lower than that of group 2 (p=0.0001, p=0.015, respectively) at 6 months postoperatively and the final follow-up. Conclusions: Although both treatments for isolated medial OCL of the talus were associated with a decrease in pain and less loss of function, single-dose HMW -HA injection following arthroscopic microfracture was significantly more effective .