Objective To investigate the clinical efficacy and mechanism of Xuefu Zhuyu Decoction in the treatment of arteriosclerosis obliterans (ASO) of the lower limbs. Methods A total of 40 patients with ASO diagnosed and treated in our department between January 2022 and January 2023 were selected. The control group received beraprost sodium, while the treatment group received both Xuefu Zhuyu Decoction and beraprost sodium. Levels of blood biochemical parameters, superoxide dismutase (SOD), malondialdehyde (MDA), oxidized low-density lipoprotein (ox-LDL), nitric oxide (NO), ankle-brachial index(ABI), and intermittent claudication distance were observed and compared before and after treatment in both groups. Results All patients in both groups were successfully treated. At baseline, there were no significant differences in age, gender, blood glucose levels, blood lipid levels, or blood pressure between the two groups before treatment. Furthermore, within the treatment group, no significant differences in blood glucose or blood lipid levels were observed before and after treatment. However, in the treatment group, while no significant difference in diastolic blood pressure was found before and after treatment, systolic blood pressure decreased significantly after treatment. After treatment, SOD levels increased significantly compared to pre-treatment levels in both group(P<0.05). The post-treatment SOD level in the treatment group showed significant improvement compared to the control group (P<0.05). MDA levels decreased significantly after treatment in both groups compared to pre-treatment levels(P<0.05). The extent of reduction in MDA levels was more significant in the treatment group than in the control group(P<0.05). After treatment, ox-LDL levels showed a decreasing trend in both groups compared to pre-treatment levels, and statistical analysis indicated a significant difference within each group (P<0.01). NO levels increased significantly in the treatment group after treatment (P=0.000), and also increased in the control group(P=0.012). Further analysis revealed that the serum NO level in the treatment group was significantly higher than that in the control group after treatment (P=0.026). After treatment, the left ABI improved significantly in the treatment group, while the right ABI improved in both groups. The intermittent claudication distance increased significantly after treatment in both groups compared to pre-treatment values. Analysis showed that the treatment group had a greater increase in intermittent claudication distance. Conclusion Xuefu Zhuyu Decoction demonstrates definite efficacy and high safety in treating ASO of the lower limbs, providing a new approach for drug therapy of this condition.