Background <p>Radial nerve palsy (RNP) is a common complication of diaphyseal humerus fractures, with primary RNP rates varying by fracture location. However, the relationship between fracture location and the risk of secondary RNP following surgical fixation remains unclear. This study aimed to evaluate the incidence of postoperative RNP based on fracture location within the middle and distal thirds of the humeral diaphysis and to describe the outcomes of RNP over time.</p> Methods <p>A retrospective cohort study was conducted of patients undergoing open reduction and internal fixation for middle and distal third diaphyseal humerus fractures at two Level 1 trauma centers from 2011 to 2023. Patients with proximal third fractures, pathologic fractures, or intramedullary nailing were excluded. Fracture location, surgical approach, and neurovascular outcomes were recorded. Differences between groups were analyzed using ANOVA and Fisher’s exact tests.</p> Results <p>A total of 164 fractures met inclusion criteria. Postoperative RNP occurred in 8% of middle third fractures, 14% of distal third fractures, and 23% of middle–distal third fractures (<i>p</i> = 0.18). Preoperative RNP was significantly more common in middle–distal third fractures (38%) compared to middle third (21%) or distal third fractures (16%) (<i>p</i> = 0.02). At final follow-up, 49% of preoperative RNPs and 78% of postoperative RNPs had resolved, with postoperative RNPs significantly more likely to recover (<i>p</i> = 0.048). No significant differences in RNP resolution were observed based on fracture location.</p> Conclusion <p>Fracture location within the middle or distal third of the humeral diaphysis was not associated with a significant difference in the incidence of postoperative radial nerve palsy following surgical fixation. Postoperative RNP demonstrated a high rate of recovery, supporting conservative management in most cases.</p> Level of Evidence <p>Level III, Retrospective Cohort Study. </p>