Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Beyond established risk factors such as smoking and exposure to pollutants increasing evidence emphasizes the role of oxidative stress (OS) in COPD pathophysiology. OS contributes to chronic inflammation, to the progression of the disease and affects both lung function and exacerbations, which opens a rationale for the use of antioxidant and redox-modulating substances in the treatment of the disease. Although numerous substances with antioxidant capacity have been evaluated in randomized clinical trials (RCTs), their clinical relevance remains uncertain. Therefore, a systematic review was conducted to evaluate the effects of these therapies in COPD. Also, a meta-analysis to evaluate the effects on exacerbations was performed. Nineteen RCTs meet the eligibility criteria and were included in the study. Quantitative analyses were performed using random-effects models. N-acetylcysteine-based interventions were associated with a significant reduction in exacerbation risk (risk ratio 0.80; 95% confidence interval 0.66–0.98), corresponding to a 20% relative reduction. No study reported serious adverse effects. These findings suggest that antioxidant-based strategies may have clinically meaningful benefits in COPD. However, larger, more robust RCTs are required to confirm these results and establish optimal therapeutic strategies.