Background Antiplatelet drugs are a cornerstone in managing atherosclerotic vascular disease (ASVD). However, their interactions with other medications present significant challenges to treatment efficacy and safety. Patients with ASVD often require multiple treatment regimens due to complex comorbidities, which increases the risk of drug-drug interactions (DDIs). These interactions can lead to drug resistance, reduced therapeutic outcomes, or adverse effects. A thorough understanding of DDIs is crucial for optimizing patient care. Aims This review aims to explore the clinical significance. mechanisms, and implications of DDIs in antiplatelet therapy Additionally, it seeks to identify future research directions to advance personalized treatment strategies and improve therapeutic outcomes. Materials and Methods A systematic literature review was conducted using key databases, focusing on clinical studies, mechanistic research, and guidelines related to antiplatelet therapy and DDIs. Findings were analyzed to identify common interaction patterns, associated risks, and management strategies. Results The review identifies common DDIs involving antiplatelet drugs, particularly with anticoagulants, nonsteroidal anti-inflammatory drugs, and proton pump inhibitors. These interactions primarily occur through pharmacokinetic mechanisms, such as alterations in drug metabolism via cytochrome P450 enzymes, and pharmacodynamic mechanisms, including synergistic or antagonistic effects on platelet inhibition. Clinically, DDIs can increase bleeding risk, reduce antiplatelet efficacy, and contribute to adverse cardiovascular outcomes. Strategies to mitigate these risks include individualized drug selection, dose adjustments, genetic testing, and therapeutic drug monitoring. Discussion Effective management of DDIs in antiplatelet therapy is essential to improve clinical outcomes. A patient-specific approach, considering comorbidities, genetic predispositions, and concurrent medications, is crucial. The review categorizes DDIs based on clinical settings and underscores the need for further research on predictive biomarkers, pharmacogenomics, and advanced monitoring techniques. Conclusion DDIs significantly impact the effectiveness and safety of antiplatelet therapy, necessitating a comprehensive understanding of their mechanisms and clinical implications. Future research should focus on developing personalized treatment approaches, integrating genetic testing, and optimizing pharmacological monitoring to minimize risks and improve therapeutic outcomes. This review provides a foundation for advancing clinical practice and enhancing the management of patients with ASVD.