not-yet-known not-yet-known not-yet-known unknown Introduction: Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder. With advancements in gene editing technology, antisense oligonucleotides (ASO) are utilized to treat DMD. These therapies partially restore dystrophin expression through exon skipping. However, the safety assessment of these drugs in clinical application remains limited. Methods: This study utilized the FDA Adverse Event Reporting System to collect reports of adverse events related to four antisense oligonucleotide drugs—Casimersen, Eteplirsen, Golodirsen, and Viltolarsen—from the third quarter of 2016 to the last quarter of 2024. The following four algorithms were used to quantify the relevant adverse events (AEs): Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma-Poisson Shrinker (MGPS) models with Empirical Bayesian Geometric Mean (EBGM). Results: Among 2,760 reports, the predominant AEs included respiratory infections, injection-site reactions, and systemic symptoms (e.g., fever, headache). A high reporting odds ratio was observed for poor venous access and product dose omission (Golodirsen, Eteplirsen, Casimersen). Proteinuria was reported for three ASOs (Viltolarsen, Eteplirsen, Casimersen). Viltolarsen exhibited the most potent signals (ROR = 55.41), compared to Eteplirsen (ROR = 31.66) and Casimersen (ROR = 8.55). Most AEs occurred more than 60 days post-dose (47–53%). Conclusions: This study confirms the overall safety of four ASO drugs in line with previous publications. Respiratory tract infections, injection site reactions, and nonspecific systemic symptoms were the most common adverse events. The adverse events such as proteinuria, heart failure, and respiratory failure highlight the importance of multidisciplinary management.