Guidelines recommend 5000U subcutaneous unfractionated heparin (UFH) for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized adults, but data comparing dosing frequencies is limited. This systematic review aimed to compare VTE and bleeding outcomes between twice daily (BID) and three times daily (TID) UFH regimens. A literature search was completed on 3/7/2024. The primary outcome was VTE occurrence (deep vein thrombosis (DVT) or pulmonary embolism (PE)). Secondary outcomes included bleeding events. Studies reporting any relevant outcomes were included, while non-human studies, reviews, non-English texts, and high VTE risk populations were excluded. Risk of bias was assessed using the Cochrane Risk-of-Bias or Newcastle-Ottawa Quality Assessment Form. Data were synthesized using Covidence and Excel. After screening, 24 studies were included: 9 observational and 15 randomized studies. Regimens with TID UFH had a 3.1% VTE occurrence (12 studies, n = 145/4653) compared to 4.0% with BID regimens (9 studies, n = 218/5426). Three times daily regimens demonstrated 4.8% DVTs (11 studies, n = 244/5102) and 0.4% PEs (11 studies, n = 24/5372), compared to 9.7% DVTs (11 studies, n = 199/2062) and 0.9% PEs (9 studies, n = 17/1974) with BID regimens. Bleeding events occurred in 3.2% of patients with BID (9 studies, n = 196/6080) and 4.3% with TID regimens (13 studies, n = 393/9044). Three times daily UFH regimens led to fewer VTE, DVT, and PE events but more bleeding compared to BID. Newer data suggests BID dosing may be more appropriate for general medical populations. Limitations include variability in data quality and publication dates. Registered with PROSPERO. No funding was received.