The choice of treatment (open reduction and internal fixation) for a humeral fracture with a plate versus an intramedullary nail is highly debated. We compared outcomes (fracture union, reoperation, and adverse events) of intramedullary nailing and plate fixation in patients with proximal humeral, humeral shaft, and distal humeral fractures. No significant differences were found between intramedullary nailing and plate fixation for fracture union, reoperation, or adverse events in patients with proximal humeral or humeral shaft fractures. There is a scarcity of evidence comparing intramedullary nailing and plating for distal humeral fractures. No recommendations can be given from current evidence. Surgeons may have to continue to use discretion based on their personal preference, experience as well as patient’s characteristics and fracture features before more high-quality evidence is available.