Nonthermal irreversible electroporation (NTIRE) is an ablation modality that utilizes microsecond electric fields to produce nanoscale defects in the cell membrane. This results in selective cell death while preserving all other molecules, including the extracellular matrix. Here, finite element analysis and experimental results are utilized to examine the effect of NTIRE on the small intestine due to concern over collateral damage to this organ during NTIRE treatment of abdominal cancers. During previous studies, the electrical treatment parameters were chosen based on a simplified homogeneous tissue model. The small intestine, however, has very distinct layers, and a more realistic model is needed to further develop this technology for precise clinical applications. This study uses a two-dimensional finite element solution of the Laplace and heat conduction equations to investigate how small intestine heterogeneities affect the electric field and temperature distribution. Experimental results obtained by applying NTIRE to the rat small intestine in vivo support the heterogeneous effect of NTIRE on the tissue. The numerical modeling indicates that the electroporation parameters chosen for this study avoid thermal damage to the tissue. This is supported by histology obtained from the in vivo study, which showed preservation of extracellular structures. The finite element model also indicates that the heterogeneous structure of the small intestine has a significant effect on the electric field and volume of cell ablation during electroporation and could have a large impact on the extent of treatment. The heterogeneous nature of the tissue should be accounted for in clinical treatment planning.