Background/Objectives: Traditional thermal ablation for pancreatic cancer is limited by collateral injury, often leading to complications such as pancreatitis. Irreversible electro-poration (IRE) is a non-thermal alternative. We investigated tissue responses in a porcine pancreas model, focusing on cell death, thermal effects, and fibrosis. Methods: Seven pigs underwent pancreatic IRE via open surgery. Local tissue temperature was monitored near the electrode. Histological evaluation included H&E, TUNEL (apoptosis), Ki-67 (prolifer-ation), vimentin (fibroblast activation), and insulin staining. Tissue remodeling was as-sessed at multiple time points up to 14 days. Results: IRE induced marked apoptosis within the ablated region, peaking at day 2. The maximum measured temperature was 78.4 °C. Over two weeks, fibrosis progressed with increased collagen and fibroblast activ-ity. Regeneration was partial, with Ki-67-positive cell proliferation and gradual loss of insulin expression, while unablated tissue showed minimal damage. Conclusions: IRE enables localized pancreatic ablation while sparing surrounding tissue. However, fibrosis limits full recovery. Limitations include small sample size, short follow-up, and species differences. Further studies are needed to refine IRE parameters and assess long-term functional outcomes.