Hippocampal injury is common in traumatic brain injury (TBI) patients, but the underlying pathogenesis remains elusive. In this study, we hypothesize that the presence of the adjacent fluid-containing temporal horn exacerbates the biomechanical vulnerability of the hippocampus. Two finite element models of the human head were used to investigate this hypothesis, one with and one without the temporal horn, and both including a detailed hippocampal subfield delineation. A fluid-structure interaction coupling approach was used to simulate the brain-ventricle interface, in which the intraventricular cerebrospinal fluid was represented by an arbitrary Lagrangian-Eulerian multi-material formation to account for its fluid behavior. By comparing the response of these two models under identical loadings, the model that included the temporal horn predicted increased magnitudes of strain and strain rate in the hippocampus with respect to its counterpart without the temporal horn. This specifically affected cornu ammonis (CA) 1 (CA1), CA2/3, hippocampal tail, subiculum, and the adjacent amygdala and ventral diencephalon. These computational results suggest the presence of the temporal horn is a predisposing factor for the prevalence of hippocampal injury, advancing the understanding of hippocampal injury during head impacts. A corresponding analysis in an imaging cohort of collegiate athletes found that temporal horn size negatively correlates with hippocampal volume in the same subfields, suggesting a possible real-world correlation whereby a larger temporal horn may be associated with decreased hippocampal volume. Our biomechanical and neuroimaging effort collectively highlight the mechanobiological and anatomical interdependency between the hippocampus and temporal horn.