Nanosecond pulsed electric field (nsPEF) exposure can disrupt and disaggregate amyloid-β, indicating its potential to improve symptoms of Alzheimer’s disease. However, the propagation and distribution patterns of nsPEF within brain tissue remain insufficiently understood, making related simulation analysis necessary. In this study, a high-resolution three-dimensional human head model incorporating the scalp, skull, cerebrospinal fluid, gray matter, white matter, and hippocampus was constructed. Based on the spectral characteristics of nsPEF, the dielectric properties of human tissues at different frequency ranges were assigned, and a transient finite-element model of nsPEF exposure in the human brain was established. The simulation analysis identified two optimal electrode-pair positions and characterized the spatial distributions of intracranial electric field strength as well as current density. It further elucidated the dependence of the hippocampal electric field response and current density on pulse parameters. In addition, a physical human brain model was constructed to experimentally validate the finite-element simulation results. The results showed that transcranial nsPEF can reach deep brain regions with extremely narrow pulse widths, and pulsed electric fields with kilovolt-level amplitudes and nanosecond-scale pulse widths can generate electric field strengths of approximately 103 V/m in the hippocampus. In summary, this work provides a theoretical basis and experimental support for optimizing the electrode configuration and stimulation parameters of transcranial nsPEF, thereby laying a foundation for future research on its application in non-invasive physical interventions for Alzheimer’s disease.