Introduction: Post-operative venous thromboembolism (VTE) prophylaxis is the standard of care after craniotomy, but there is debate over when to initiate VTE prophylaxis to decrease the morbidity and mortality experienced by these patients. This study aims to determine the effects of starting enoxaparin on day one vs. day three after craniotomy.Methods: We used a multi-institutional health research network (TriNetX) to gather data from the electronic medical records of patients who started enoxaparin one day after craniotomy (cohort 1) and patients who started it three days later (cohort 2). Our primary endpoint was mortality, with the secondary endpoints of deep venous thrombosis (DVT), additional craniotomy, pulmonary embolism (PE), myocardial infarction (MI), ischemic stroke (IS), intracerebral hemorrhage (ICH), ventilator and tracheostomy dependence, or percutaneous endoscopic gastrostomy (PEG) tube dependence. Patients were propensity score-matched for demographics, common comorbidities, and anticoagulant and antiplatelet use.Results: After propensity score matching, 1,554 patients were identified in each cohort. In cohort 1, 21.171% of patients were deceased after five years vs. 26.126% in cohort 2 (p= 0.0012; OR 0.759, 95% CI (0.643,0.897)). The 30-day survival was 94.521% vs. 93.049%, the 90-day survival was 90.200% vs. 87.335%, and the 365-day survival was 80.619 vs. 76.817%. Deep venous thrombosis occurred in 5.277% of cohort 1 and 7.851% of cohort 2 (p=0.0038, OR 0.654, 95% CI [0.49,0.873]). There was no increase in intracerebral hemorrhage in cohort 1. There were no statistically significant differences in subsequent craniotomy rates, PE, MI, IS, ventilator/tracheostomy, or PEG tube dependence.Conclusion: Starting enoxaparin on day one after craniotomy was associated with decreased mortality and DVTs, with no difference in rates of PE, MI, IS, tracheostomy/PEG dependence, or further craniotomy.