This study aimed to evaluate the efficacy of a combined treatment approach integrating extensive debridement, immediate internal fixation, and the Masquelet technique for the management of infected nonunion of long bones in the lower limbs caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria. This retrospective case series was conducted at the Imam Khomeini Hospital Complex, Tehran, Iran, a tertiary-level academic referral centre. The study documented consecutive cases of patients presenting with infected nonunion of the tibia or femur, with a positive culture for MDR or XDR bacteria, treated between January 2019 and December 2022. Inclusion criteria were adults with a confirmed diagnosis of infected nonunion due to MDR or XDR bacteria, with exclusion criteria including patients with unrelated infections or allergies to the components of the treatment regimen. The primary outcomes measured were infection resolution and bone healing. The study cohort comprised 16 patients, predominantly male (87.5%) with an average age of 38.5 years. Methicillin-resistant Staphylococcus aureus (MRSA) was identified as the causative agent in 31.25% of the infections. Patients were followed for a period ranging from 12 to 26 months. The treatment protocol was uniformly applied across all cases. Successful bone union was observed in the majority of patients within 140 to 240 days following grafting. However, there were two instances where amputation was necessitated due to the failure to eradicate the infection. Complications arose in three cases during the follow-up period: two required re-debridement due to a recurrence of the infection, and one was subjected to bone transport owing to persistent nonunion. Notably, all cases that either failed or encountered complications were smokers. In this integrated approach, high rates of infection resolution and bone healing were achieved, suggesting this method as a viable option for these complex cases.