Objective To evaluate the efficacy and safety of sulodexide injection and low molecular weight heparin (LMWH) in the treatment of patients with lower extremity atherosclerotic Obliterans (LEASO). Methods This retrospective study included LEASO patients who underwent endovascular revascularization surgery at Peking University Shenzhen Hospital from April 2022 to April 2024. Based on postoperative anticoagulation therapy, patients were divided into the observation group (sulodexide injection, n=144) and the control group (LMWH, n=138). Observed parameters included coagulation function [Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), D-dimer, Thrombin Time (TT), Platelet Count (PLT)], inflammatory factors[C-Reactive Protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α)], hemodynamic indices[Ankle-Brachial Index (ABI), Toe-Brachial Index (TBI)], walking function[Maximum Walking Distance (MWD) and Pain-Free Walking Distance (PFWD)], and pain score [Visual Analog Scale (VAS)]. Treatment efficacy and safety were compared between the two groups. Results The observation group demonstrated significant by better improvements in coagulation function (D-dimer decreased by 29.4%, P=0.021), inflammatory factors (IL-6 decreased by 38.1%, P=0.018), and hemodynamic indices (ABI increased by 20.0%, P=0.004) compared to the control group. Sulodexide significantly enhanced maximum walking distance (MWD) (+30.0%, P=0.016) and alleviated pain (VAS decreased by 43.4%, P=0.004). Conclusion Sulodexide injection, through its multitarget mechanism, demonstrates superior efficacy in postoperative anticoagulation therapy for LEASO, particularly in improving coagulation function, alleviating inflammation, and enhancing hemodynamics. It also exhibits good safety, making it a promising first-line option for anticoagulation in LEASO patients.