Recent studies have revealed extensive neocortical pathology in multiple sclerosis (MS). The hippocampus is a unique archaeocortical structure understudied in MS. It plays a central role in episodic and anterograde memory—the most frequently impaired cognitive modalities in MS. This histopathological study aimed to investigate inflammatory demyelination and neurodegenerative changes in the MS archaeocortex. A detailed quantitative analysis was performed on hippocampal autopsy tissue from 45 progressive MS cases and seven controls. Forty-one lesions were identified in 28 of the 45 hippocampal MS-blocks examined, with percentage area of demyelination averaging 30.4%. The majority of lesions were chronic and subpially or subependymally located. Compared to controls, neuronal numbers were decreased by 27% in CA1 and 29.7% in CA3-2. Furthermore, the size of neurones was decreased by 17.4% in CA1. There was evidence of gross hippocampal atrophy with a 22.3% reduction in the average cross-sectional area, which correlated with neuronal loss. Our study provides evidence of substantial archaeocortical pathology largely resembling patterns seen in the neocortex and suggests that hippocampal involvement could contribute to memory impairments often seen in MS.