Aim The present study is aimed at evaluating the effect of combined treatment on massive bone defect using radical debridement, antibiotic calcium sulphate, and monolateral external fixator. Methods 35 patients with tibial osteomyelitis received radical debridement, and during surgery antibiotics-impregnated calcium sulphate was used for filling the bone defect. Monolateral external fixator was used to manage the bone defect of average 95 (61-185) cm. Results Bone union was achieved in 34 patients (97.1%) with no reinfection. One case was presented with reinfection and further debridement was conducted. The average time for the utility of external fixation was 17 (7-32) months, and external fixation index (EFI) was 1.79 mon/cm. The mean follow-up duration after surgery was 33.7 (21-41) months. 19, 13, and 3 patients got excellent, good, and fair bone results, respectively. Meanwhile, functional results were excellent, good, fair, and poor in 13, 15, 6, and 1 patient. The most common complication was pain (100%) and superficial pin-tract infection (22.8%). Delayed maturation was incurred in 2 patients. Conclusion Our study reveals that radical debridement combined with antibiotics-impregnated calcium sulphate can suppress infection, and distraction osteogenesis using monolateral external fixators plays an effective role in managing osteomyelitis-induced massive tibial bone defect.