Hyperbaric oxygen (HBO) is a major therapeutic treatment for ischemic ulcerations that perforate skin and underlying muscle in diabetic patients. These lesions do not heal effectively, in part, because of the hypoxic microvascular O₂ partial pressures (PmvO₂) resulting from diabetes-induced cardiovascular dysfunction which alters the dynamic balance between O₂ delivery and utilization rates. We tested the hypothesis that HBO in diabetic muscle would exacerbate the hyperoxic PmvO₂ dynamics due, in part, to a reduction or slowing of the cardiovascular, sympathetic nervous and respiratory system responses to acute HBO exposure. Adult male Wistar rats were divided randomly into diabetic (DIA: Streptozotocin i.p.) and healthy (CONT) groups. A small animal hyperbaric chamber was pressurized with oxygen (100% O₂) to 3.0 ATA at 0.2 ATA/min. Phosphorescence quenching techniques were used to measure PmvO₂ in tibialis anterior muscle of anesthetized rats during HBO. Lumbar sympathetic nerve activity (LSNA), heart rate (HR) and respiratory rate (RR) were measured electrophysiologically. During the normobaric hyperoxia and HBO, DIA tibialis anterior PmvO₂ increased faster than CONT. Subsequently, PmvO₂ remained elevated at similar levels in CONT. Sympathetic nervous system, cardiac and respiratory responses to HBO were slower in DIA versus CONT. HBO treatment increases tibialis anterior muscle PmvO₂ more rapidly and for a longer duration in DIA than CONT, but not to a greater level. Whereas, respiratory, cardiovascular and LSNA responses to HBO are profoundly slowed in DIA only the cardiovascular arm (via HR) may contribute to the muscle vascular incompetence and these faster PmvO₂ kinetics.