Background: Free flaps have been a useful modality in the management of lower extremity osteomyelitis particularly in limb salvage. This study aimed to determine the factors affecting the outcome of free flap reconstruction in the treatment of osteomyelitis. Methods: This retrospective study assessed 65 osteomyelitis patients treated with free flap transfer from 2015 to 2020. The treatment outcomes were evaluated in terms of the flap survival rate, recurrence rate of osteomyelitis, and amputation rate. The correlation between outcomes and comorbidities, causes of osteomyelitis, and treatment modalities was analyzed. The following factors were considered: smoking, peripheral artery occlusive disease, renal disease, diabetic foot ulcer, flap types, using antibiotic beads, and negative pressure wound therapy. Result: Among the 65 patients, 21 had a severe peripheral arterial occlusive disease. Osteomyelitis developed from diabetic foot ulcers in 28 patients. Total flap failure was noted in six patients, and osteomyelitis recurrence was noted in eight patients, for which two patients underwent amputation surgery during the follow-up period. Only end-stage renal disease had a significant correlation with the recurrence rate (odds ratio = 16.5, p = 0.011). There was no significant relationship between outcomes and the other factors. Conclusion: This study showed that free flaps could be safely used for the treatment of osteomyelitis in patients with comorbidities and those who had osteomyelitis developing from diabetic foot ulcers. However, care should be taken in patients diagnosed with end-stage renal disease.