Introduction: Prophylactic surgical drains are commonly used in Nigeria following intramedullary nailing (IMN) of long bone diaphyseal fractures. However, evidence in the literature suggests that drains do not confer any benefit and predispose clean wounds to infection. This study compares outcomes between patients treated with and without prophylactic surgical drainage following diaphyseal long bone fractures treated with IMN. Methods: A prospective cohort study with randomization was conducted at a tertiary referral center in Enugu, Nigeria. Investigators included skeletally mature patients with diaphyseal long bone (femur, tibia, humerus) fractures treated with SIGN IMN. Patients followed-up at 5, 14, and 30 days post-operatively. The primary outcome was surgical site infection (SSI) rate. Secondary outcomes included post-operative pain at 6 and 12 h, need for blood transfusion, wound characteristics (swelling, ecchymosis, and gaping), need for dressing changes, and length of hospital stay. Results: Of the enrolled patients, 76 (96%) of 79 completed 30-day follow-up. SSI rate was associated with patients who received a prophylactic drain versus those who did not (23.7% vs. 10.5%, p = 0.007). There were no significant differences in transfusion need (p = 0.22), wound swelling (p = 0.74), wound ecchymosis (p = 1.00), wound gaping (p = 1.00), dressing change need (p = 0.31), post-operative pain at 6 h (p = 0.25) or 12 h (p = 0.57), or length of stay (p = 0.95). Discussion: Surgical drain placement following IMN of diaphyseal long bone fractures is associated with a significantly higher risk of SSI. Reducing surgical drain use following orthopaedic injuries in lower resource settings may translate to reduced infection rates.