Objective: To evaluate the antioxidant capacity, anti-inflammatory effects, and potential side effects of synthetic and natural antioxidants in controlling oxidative stress in inflammatory conditions. Methodology: This study aimed to compare the efficacy of synthetic and natural antioxidants in reducing oxidative stress and inflammation in 100 individuals with inflammatory diseases. A randomized controlled trial was conducted with participants assigned to either a synthetic antioxidant group or a natural antioxidant group, with assessments at baseline, 3 months, and 6 months. Key outcomes measured included reactive oxygen species (ROS), inflammatory markers (C-reactive protein [CRP] and tumor necrosis factor-alpha [TNF-α]), and Disease Activity Score (DAS28). Statistical analyses, including t-tests, ANOVA, and multivariate regression, were employed to compare the changes in these markers between the two groups over time. Result: The results revealed that both antioxidant groups experienced significant reductions in ROS, CRP, and TNF-α, with the natural antioxidant group showing a more pronounced improvement. At 6 months, the natural antioxidant group exhibited a 53.5% reduction in ROS levels, compared to a 40% reduction in the synthetic antioxidant group. Similarly, the natural antioxidant group showed greater reductions in CRP and TNF-α, and a significantly lower DAS28 score (2.7) compared to the synthetic antioxidant group (3.5). Statistical significance was observed at both the 3-month (p = 0.04) and 6-month (p = 0.02) time points for disease activity. Conclusion: Natural antioxidants demonstrated superior efficacy in reducing oxidative stress, inflammation, and disease activity compared to synthetic antioxidants. These findings suggest that natural antioxidants may offer a more effective and comprehensive therapeutic approach for managing inflammatory diseases, potentially leading to better long-term clinical outcomes. Further research is warranted to explore the underlying mechanisms and the broader applicability of natural antioxidants in clinical practice.