Aim Further to its pivotal role in haemostasis, factor Xa (FXa) promotes effects on the vascular wall. The purpose of the study was to evaluate if FXa modifies the expression level of energy metabolism and oxidative stress‐related proteins in femoral arteries obtained from type 2 diabetic patients with end‐stage vasculopathy. Methods Femoral arteries were obtained from 12 type 2 diabetic patients who underwent leg amputation. Segments from the femoral arteries were incubated in vitro alone and in the presence of 25 nmol l−1 FXa and 25 nmol l−1 FXa + 50 nmol l−1 rivaroxaban. Results In the femoral arteries, FXa increased triosephosphate isomerase and glyceraldehyde‐3‐phosphate dehydrogenase isotype 1 expression but decreased pyruvate dehydrogenase expression. These facts were accompanied by an increased content of acetyl‐CoA. Aconitase activity was reduced in FXa‐incubated femoral arteries as compared with control. Moreover, FXa increased the protein expression level of oxidative stress‐related proteins which was accompanied by an increased malonyldialdehyde arterial content. The FXa inhibitor, rivaroxaban, failed to prevent the reduced expression of pyruvate dehydrogenase induced by FXa but reduced acetyl‐CoA content and reverted the decreased aconitase activity observed with FXa alone. Rivaroxaban + FXa but not FXa alone increased the expression level of carnitine palmitoyltransferase I and II, two mitochondrial long chain fatty acid transporters. Rivaroxaban also prevented the increased expression of oxidative stress‐related proteins induced by FXa alone. Conclusions In femoral isolated arteries from type 2 diabetic patients with end‐stage vasculopathy, FXa promoted disruption of the aerobic mitochondrial metabolism. Rivaroxaban prevented such effects and even seemed to favour long chain fatty acid transport into mitochondria.