Peripheral Artery Disease (PAD) represents the manifestation of atherosclerosis and its complications affecting lower extremity arteries, leading to cardiovascular (CV) events. Currently, around 230 million people are affected by PAD worldwide, and its prevalence increases according to age and CV comorbidities. Among guidelines-directed medical therapy (GDMT), antithrombotic agents play a central role in the management of patients with PAD, aiming to reduce the risk of major adverse cardiovascular events (MACE) such as myocardial infarction, stroke, and CV death, as well as major adverse limb events (MALE), including acute limb ischemia and amputation. The current international guidelines recommend antiplatelet therapy, particularly with aspirin or clopidogrel, as first-line treatment in patients with symptomatic PAD to mitigate the CV risk. The CAPRIE trial demonstrated the superiority of clopidogrel over aspirin in reducing MACE in patients with atherosclerotic disease, including PAD. Other antithrombotic strategies such as dual antiplatelet therapy (DAPT) are typically reserved for specific indications, including patients with recent concomitant coronary revascularization, or high ischemic risk without high bleeding risk. Recent evidence has highlighted the role of dual pathway inhibition (DPI), combining low-dose rivaroxaban with aspirin therapy. The COMPASS trial showed that rivaroxaban 2.5 mg twice daily plus aspirin significantly reduced the risk of MACE and MALE compared to aspirin alone in patients with stable atherosclerotic cardiovascular disease, including PAD. Moreover, the VOYAGER-PAD trial demonstrated that rivaroxaban combined with aspirin reduced ischemic events following lower extremity revascularization without substantially increasing severe bleeding risks. Despite these advances, optimal antithrombotic strategies require careful balancing of ischemic and bleeding risks, particularly in patients with comorbidities such as diabetes, chronic kidney disease, or a history of bleeding. Ongoing research is focused on refining patient selection for intensive antithrombotic regimens and exploring novel agents to further improve outcomes as well as optimizing strategies to improve the prescription and the adoption of GDMT, including antithrombotic therapy.