Background: Type 2 diabetes mellitus (T2DM)-induced neuropathy and ischemia-reperfusion post-surgery prolong carpal tunnel syndrome (CTS) pathology, but the effect of T2DM on the prognostic outcome of carpal tunnel (CT) release surgery needs to be investigated. Materials and methods: A total of 64 individuals with CTS underwent CT release surgery. HbA1c levels identified their diabetic status. The individual prognostic outcomes were measured by nerve conduction velocity (NCV), amplitude, and latency. Measurement of [Ca 2+ ] c and reactive oxygen species (ROS) from isolated endothelial cells (ECs) revealed the oxidative burden of the normal and diabetic CTS phenotypes. Results: CTS individuals with HbA1c > 7 showed decreased NCV (≈22 m/s) and amplitude (≈4.2 mV) with increased latency (≈6 ms), compared to groups with HbA1c ≤ 7. Further to CT release surgery, the reversal of the nerve conduction to normalcy was greatly influenced by the diabetic profile of the individuals. Our results showed elevated basal [Ca 2+ ] c and corresponding high cytosolic ROS in the ECs isolated from individuals with HbA1c > 7 compared to the diabetic and healthy control groups. Conclusion: The individuals with diabetic index showed suboptimal neuronal performance pre-and post-CT release surgery. Oxidative stress mediated by high [Ca 2+ ] c and ROS of ECs dissipates to adjoining cells worsening the pathology of the untreated CTS.