The human hippocampus, a critical structure nestled within the medial temporal lobe, plays an indispensable role in functions ranging from memory formation to spatial navigation. Neuropathological alterations in the hippocampus can profoundly affect these cognitive abilities, contributing to various neurological and psychiatric disorders. This chapter delves into the intricate neuropathology of the hippocampus, exploring its vulnerability to a spectrum of diseases such as Alzheimer’s disease, temporal lobe epilepsy, and ischemic injury. Through a detailed examination of morphological changes, molecular dysregulations, and resultant clinical implications, we aim to enhance understanding of the pathological processes that affect this vital brain region, providing insights into potential therapeutic targets and diagnostic markers.