This systematic review and meta-analysis aimed to compare the outcomes of intramedullary nailing (IMN) and open reduction with internal fixation (ORIF) in treating traumatic humeral shaft fractures in adults (18 years and above). A comprehensive literature search was conducted in databases including PubMed, Google Scholar, Embase, and CochraneCentral Register of Controlled Trials (CENTRAL). The primary outcome was time to union, while secondary outcomes included non-union rates, incidences of iatrogenic radial nerve palsy, surgical site infections, and intra-operative comminution. Twenty-six studies, encompassing 1,674 patients (867 IMN, 807 ORIF), were included. IMN demonstrated a shorter time to union compared to ORIF (mean difference -1.06 (95% CI, -1.88 to -0.23)), with significant statistical heterogeneity (I² = 70%), and a mean difference of -2.14 (95% CI, -3.16 to -1.12) in the randomized controlled trial (RCT) subgroup analysis, which had no significant statistical heterogeneity. Both techniques had comparable non-union rates (risk ratio 0.34 (95% CI, 0.94 to 1.93)). IMN was associated with lower incidences of iatrogenic radial nerve palsy (risk ratio 0.48 (95% CI, 0.27 to 0.87)) and surgical site infections (risk ratio 0.44 (95% CI, 0.25 to 0.76)), but had a higher risk of intra-operative comminution (risk ratio 3.04 (95% CI, 1.24 to 7.44)). The studies exhibited significant heterogeneity and varying outcome measures, highlighting the need for cautious interpretation. IMN offers rapid fracture stabilization and minimal additional physiological insult, while ORIF remains preferable for achieving precise anatomical reduction. These findings highlight the importance of considering patient-specific factors and surgical expertise in selecting the appropriate fixation technique.