Aim: Complex atherosclerotic femoro-popliteal lesions have traditionally been treated with bypass surgery. A prosthetic graft is used to save the vein graft for more distal revascularisations or when a vein graft is unavailable. The endovascular approach has gained popularity and is offered as a first-line strategy for complex lesions. This study aimed to evaluate whether endovascular procedures can be used as a first-line treatment strategy for complex native femoro-popliteal lesions over open surgery with prosthetic bypass in patients with peripheral arterial disease (PAD). Methods: This single-centre retrospective observational study was conducted between 2013 and 2021; it included patients with symptomatic PAD who required limb revascularisation at the femoro-popliteal segment and who had complex lesions. The primary endpoints analysed were technical success, primary patency, freedom from clinically driven target lesion revascularisation (cdTLR), freedom from major adverse limb and cardiovascular events (MALE and MACE, respectively), freedom from limb loss, and survival. The secondary endpoints were length of in-hospital stay, and duration and costs of the procedure. Results: We identified 185 limbs among 174 suitable candidates for comparison, wherein 105 were treated with an endovascular procedure and 80 with a femoro-popliteal prosthetic bypass. Most patients in both groups presented with chronic limb-threatening ischaemia, and >90% of them had an American Society of Anesthesiologists (ASA) physical status classification of >3. The endovascular group had more octogenarians (p = 0.02) and patients with coronary disease (p = 0.004). The median follow-up was 30 months. The technical failure rate for endovascular procedures was 4.7%, versus 0% in the open group (p = 0.047). Freedom from MACE was similar in both groups. The endovascular group showed superior primary patency (p < 0.0001), cdTLR (p < 0.0001), MALE (p < 0.0001), and freedom from limb loss (p = 0.0018) at 24 and 48 months. Further analysis performed for the open above-the-knee sub-group showed that the aforementioned endpoints were similar between the groups at 12 months and were better in the endovascular group at 24 and 48 months. Procedural time and in-hospital stay were longer in the open group than in the endovascular group (p < 0.0001 and p < 0.001, respectively). The procedural cost in the endovascular group was 10-fold lower than that in the prosthetic bypass group. Conclusions: Endovascular procedures are safe for treating complex femoro-popliteal lesions in patients at a high risk for surgery and show better outcomes at 24 months than prosthetic bypasses do. The latter may be considered as an alternative should endovascular treatment fail.