BACKGROUND: The COVID-19 pandemic has led to the widespread use of anticoagulation (AC) and corticosteroids (CCS) for hospitalized patients, but real-world outcomes may differ from clinical trial findings due to diverse patient populations and treatment variability. OBJECTIVE: To evaluate the real-world impact of AC and CCS therapies on key clinical outcomes in hospitalized COVID-19 patients. DESIGN: Multicenter, retrospective observational cohort study conducted across 11 hospitals in a Midwest health system. PARTICIPANTS: The study included 4,754 hospitalized COVID-19 patients treated with AC, CCS, both (AC+CCS), or neither. The 'neither' group served as the reference for comparisons. INTERVENTIONS: Interventions included administration of AC, CCS, both AC+CCS, or no intervention. MAIN MEASURES: Primary outcomes included thromboembolism (TE), bleeding events, ICU admissions, invasive mechanical ventilation (IMV), and in-hospital mortality. KEY RESULTS: Compared to the reference group, the AC+CCS group had significantly lower odds of TE (aOR 0.61, 95% CI 0.43-0.87) and bleeding events (aOR 0.15 95% CI (0.08, 0.27)). The AC-only group demonstrated the lowest ICU admission, IMV, and mortality rates (aHR 0.30 95% CI (0.17, 0.53)). The CCS-only group had the highest rates of adverse outcomes, likely reflecting greater baseline illness severity. CONCLUSIONS: This study emphasizes the importance of individualized treatment strategies in hospitalized COVID-19 patients, showing that real-world outcomes of AC and CCS can differ significantly from controlled trials. These findings provide crucial insights for adapting clinical guidelines to diverse patient settings.