Objective To compare drug (paclitaxel)-coated balloon angioplasty with femoropopliteal bypass surgery in the treatment of femoropopliteal lesions. Methods A retrospective study was performed between January 2015 and January 2019, covering a four-year period. All subjects who underwent femoropopliteal bypass surgery and drug-coated balloon angioplasty over a four-year period were evaluated. The subjects’ demographic characteristics, lesion characteristics, treatment outcomes and disease-free survival were collected. Subjects were divided into the femoropopliteal bypass group (Group A) and the drug-coated balloon angioplasty (Group B) group. Results In total, 220 subjects were enrolled. Both Group A and Group B consisted of 110 subjects. The proportion of patients with a claudication distance between 0 and 50 m was significantly higher in Group A, and the proportion of patients with a claudication distance between 50 and 100 m was significantly higher in Group B ( p = 0.001). In terms of the Rutherford levels, moderate claudication was significantly higher in Group B, and severe claudication was significantly higher in Group A ( p = 0.001). The lesion length for the subjects in Group A was significantly longer than that in Group B (24.61 ± 2.79 mm for Group A and 18.59 ± 3.95 mm for Group B, p = 0.001). The stenosis degree in Group A was also significantly higher than that in Group B (96.82 ± 4.32% for Group A and 94.85 ± 4.55% for Group B, p = 0.001). The duration of the procedure, duration of hospitalization and rate of bleeding in Group A were significantly higher than those in Group B. The incidence of overall morbidity and reintervention rates in Group B were significantly higher than that in Group A. The preoperative ankle brachial index values of the subjects in Group B were statistically significantly higher than those in Group A (0.56 ± 0.08 for Group A and 0.61 ± 0.08 for Group B, p = 0.001). The change in the ankle brachial index measurement of the subjects in Group A with respect to the preprocedure value was significantly greater than that in Group B ( p = 0.001). For primary patency, there was a significant difference between the groups in the distribution of the duplex ultrasound results at the 3rd, 6th, 9th and 12th month control points ( p = 0.001). At all control points, Group A had better primary patency rates, whereas the secondary patency rates did not differ. In total, among the 220 patients, 125 (56.8%) were disease free, and 95 (43.2%) experienced recurrence. The mean disease-free survival times for Group A and Group B were 10.45 ± 0.28 months and 9.11 ± 0.37 months, respectively. The disease-free survival rates were significantly higher in Group A ( p = 0.001, p < 0.05). Conclusion Femoropopliteal bypass resulted in better disease-free survival rates than drug-coated balloon angioplasty and serves as an effective modality for the treatment of femoropopliteal lesions.