Background: Humeral shaft fractures (HSFs) represent 13–25% of humeral fractures and are frequently complicated by radial nerve palsy and nonunion. While conservative management was historically preferred, surgical fixation with intramedullary nailing (IMN) has gained increasing popularity. The aim of this study was to evaluate the effectiveness of IMN in the treatment of HSFs, focusing on postoperative complications and functional outcomes. Methods: A bicenter retrospective analysis was conducted on 202 patients who underwent antegrade IMN fixation for HSF between 2014 and 2019, with a minimum follow-up of four years. Demographic data, trauma characteristics, surgical details, and postoperative complications were recorded. Functional outcomes were assessed at one year using the Disabilities of the Arm, Shoulder and Hand (DASH), Oxford Shoulder Score (OSS), Constant Shoulder Score (CSS), and Visual Analogue Scale (VAS). Statistical analysis included ANOVA, Student’s t-test, Spearman’s correlation, and multivariate regression. Results: The mean follow-up was 57.7 ± 19.6 months. At one year, mean OSS, DASH, CSS, and VAS scores were 39.0, 16.6, 73.5, and 0.9, respectively. Excellent or good Constant outcomes were recorded in 89.6% of patients. Sixteen complications (7.9%) occurred, including nerve injuries (4.0%) and pseudoarthrosis (1.5%). Patients operated within 48 h had significantly better functional scores compared to those treated later (p < 0.01). No differences were found according to fracture pattern, sex, diabetes, or osteoporosis. Age showed a weak correlation with functional outcomes. Conclusions: IMN is a safe and effective option for the treatment of HSFs, with high rates of functional recovery and a low incidence of complications. Early surgical intervention appears to improve outcomes, supporting its role as a valuable strategy in HSF management.