Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease requiring corticosteroids for symptom control, but long-term use is associated with adverse effects. The efficacy of alternate-day corticosteroid regimens compared to daily dosing remains unclear, particularly in disease activity reduction and side effect mitigation. Objective: To compare the efficacy of daily versus alternate-day prednisolone regimens in reducing disease activity in RA patients, measured by Disease Activity Score-28 (DAS-28), and to assess metabolic adverse effects. Methods: This randomized controlled trial included 108 RA patients (n = 54 per group) meeting the 2010 ACR/EULAR criteria. Participants were randomized to receive either 7.5 mg daily or 15 mg alternate-day prednisolone for six weeks. The primary outcome was DAS-28 reduction, with secondary outcomes including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and adverse events. Ethical approval was obtained (IRB/2023-RA-019), and statistical analysis was performed using SPSS v27, employing independent t-tests and Chi-square tests with Bonferroni correction. Results: DAS-28 scores decreased significantly in both groups (daily: 4.5 ± 1.2 to 3.2 ± 1.0; alternate-day: 4.3 ± 1.1 to 3.0 ± 0.9, p = 0.73). No significant differences were observed in ESR (p = 0.61), CRP (p = 0.52), or adverse events (p > 0.05). Conclusion: Both dosing regimens effectively reduce disease activity, with alternate-day dosing showing comparable efficacy and potentially fewer metabolic side effects. Future studies should evaluate long-term outcomes and individualized corticosteroid strategies.