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Introduction Venous thromboembolism (VTE) is the primary cause of preventable death in hospitalized patients in the United States. This is a cross-sectional study with a brief cost analysis of thromboprophylaxis with rivaroxaban and enoxaparin in acutely ill medical inpatients. Methods The study included a total of 122 patients admitted to a public teaching hospital from December 2019 to January 2021. The sample was equally divided into two groups according to the thromboprophylactic agent prescribed: rivaroxaban or enoxaparin. The primary outcomes included bleeding and symptomatic, ultrasonography-confirmed arterial or venous thrombotic events during or within 90 days after hospitalization. Our secondary outcome was the direct costs of each anticoagulant in US dollars over the 14 months. Results During hospitalization, two events were detected in the enoxaparin group: minor bleeding with minimum intervention required (1.6%) and a deep vein thrombosis (DVT) case (1.6%) confirmed by ultrasonography. Within 90 days after discharge, two patients, one of each sample (1.6% vs. 1.6%), were readmitted due to confirmed acute arterial occlusion. Concerning financial assessment, the mean unit cost of enoxaparin during the 14 months assessed was 102.14% more expensive than rivaroxaban. Conclusions Both rivaroxaban and enoxaparin showed equivalence in effectiveness and safety in thromboprophylaxis in medical inpatients, aside from possible financial benefit with the first-mentioned drug.