Metabolic syndrome (MS) in obese Zucker rats (OZR) is associated with impaired skeletal muscle performance and blunted hyperemia. Studies suggest that reduced O₂ diffusion capacity is required to explain compromised muscle performance and that heterogeneous microvascular perfusion distribution is critical. We modeled tissue oxygenation during muscle contraction in control and OZR skeletal muscle using physiologically realistic relationships. Using a network model of Krogh cylinders with increasing perfusion asymmetry and increased plasma skimming, we predict increased perfusion heterogeneity and decreased muscle oxygenation in OZR, with partial recovery following therapy. Notably, increasing O₂ delivery had less impact on VO₂ than equivalent decreases in O₂ delivery, providing a mechanism for previous empirical work associating perfusion heterogeneity and impaired O₂ extraction. We demonstrate that increased skeletal muscle perfusion asymmetry is a defining characteristic of MS and must be considered to effectively model and understand blood-tissue O₂ exchange in this model of human disease.