Aim: This study aimed to compare the efficacy, safety, and patient outcomes of intravenous (IV) iron therapy versus oral iron supplementation in the management of anemia of chronic disease (ACD). Materials and Methods: A total of 100 patients diagnosed with ACD were randomly assigned to two groups. Group A received IV iron therapy with iron sucrose (200 mg twice weekly for three weeks), while Group B received oral iron supplementation with ferrous sulfate (325 mg twice daily for 12 weeks). Hemoglobin levels, serum ferritin, and transferrin saturation were evaluated at baseline and at 4, 8, and 12 weeks. Adverse events and treatment satisfaction were also recorded. Statistical analysis was conducted using independent t-tests and chi-square tests, with a significance threshold of p < 0.05. Results: Baseline characteristics were comparable between the groups. At 12 weeks, Group A demonstrated significantly greater improvements in hemoglobin levels (11.7 ± 0.7 g/dL vs. 10.5 ± 0.8 g/dL, p < 0.01) and ferritin levels (110.7 ± 9.8 ng/mL vs. 80.9 ± 9.6 ng/mL, p < 0.01) compared to Group B. Adverse events were more common in Group B, with 30% experiencing gastrointestinal discomfort compared to 8% in Group A (p < 0.01). Patient satisfaction was significantly higher in Group A (88%) compared to Group B (64%, p < 0.01). Conclusion: Intravenous iron therapy was more effective and better tolerated than oral iron supplementation in the treatment of anemia of chronic disease. IV iron therapy is a preferred option, particularly for patients with moderate to severe anemia or those who do not respond to oral iron.