While high-velocity missile injury (gunshot) is associated with kinetic and thermal injuries, non-missile penetrating head injury (NMPHI) results in primary damage along the tract of the piercing object that can be associated with significant secondary complications. Despite the unique physical properties of NMPHI, factors associated with complications, expected outcomes, and optimal management have not been defined. In this study, the authors attempted to define those factors. Consecutive adult patients with NMPHI who presented to Tygerberg Academic Hospital (Cape Town, South Africa) in the period from August 1, 2011, through July 31, 2018, were enrolled in a prospective study using a defined treatment algorithm. Clinical, imaging, and laboratory data were analyzed. One hundred ninety-two patients (185 males [96%], 7 females [4%]) with 192 NMPHIs were included in this analysis. The mean age at injury was 26.2 ± 1.1 years (range 18-58 years). Thirty-four patients (18%) presented with the weapon in situ. Seventy-one patients (37%) presented with a Glasgow Coma Scale (GCS) score of 15. Weapons included a knife (156 patients [81%]), screwdriver (18 [9%]), nail gun (1 [0.5%]), garden fork (1 [0.5%]), barbeque fork (1 [0.5%]), and unknown (15 [8%]). The most common wound locations were temporal (74 [39%]), frontal (65 [34%]), and parietal (30 [16%]). The most common secondary complications were vascular injury (37 patients [19%]) and infection (27 patients [14%]). Vascular injury was significantly associated with imaging evidence of deep subarachnoid hemorrhage and an injury tract crossing vascular territory (p ≤ 0.05). Infection was associated with delayed referral (> 24 hours), lack of prophylactic antibiotic administration, and weapon in situ (p ≤ 0.05). A poorer outcome was associated with a stab depth > 50 mm, a weapon removed by the assailant, vascular injury, and eloquent brain involvement (p ≤ 0.05). Nineteen patients (10%) died from their injuries. The Glasgow Outcome Scale (GOS) score was linearly related to the admission GCS score (p < 0.001). One hundred forty patients (73%) had a GOS score of 4 or better at discharge. The most common NMPHI secondary complications are vascular injury and infection, which are associated with specific NMPHI imaging and clinical features. Identifying these features and using a systematic management paradigm can effectively treat the primary injury, as well as diagnose and manage NMPHI-related complications, leading to a good outcome in the majority of patients.