The surgical treatment of septic non-union is challenging and carries a high failure rate. Bone defect management and fracture site stabilisation are key treatment objectives. We report the case of a 75-year-old woman who underwent intercalary endoprosthetic reconstruction of a large tibial defect due to septic non-union after two previous treatment failures. The two-stage procedure involved extensive excision of infected tissues and implantation of an antibiotic-loaded cement spacer followed by insertion of an intercalary endoprosthesis. Within only 2 months after the procedure, the patient was able to walk with no assistive device and no limp. After 12 months and 6 months after antibiotic discontinuation, the laboratory tests and imaging studies showed no evidence of infection. Intercalary endoprosthetic reconstruction may be a valid treatment option to avoid amputation for recurrent septic non-union, particularly in elderly patients.