The hippocampus plays an important role in maintaining normal cognitive function and is closely associated with the neuropathogenesis of dementia. Wnt signaling is relevant to neuronal development and maturation, synaptic formation, and plasticity. The role of Wnt10a in hippocampus-associated cognition, however, is largely unclear. Here, we examined the morphological and functional alterations in the hippocampus of Wnt10a-knockout (Wnt10a) mice. Neurobehavioral tests revealed that Wnt10a mice exhibited spatial memory impairment and anxiety-like behavior. Immunostaining and Western blot findings showed that the protein expressions of β-catenin, brain-derived neurotrophic factor, and doublecortin were significantly decreased and that the number of activated microglia increased, accompanied by amyloid-β accumulation, synaptic dysfunction, and microglia-associated neuroinflammation in the hippocampi of Wnt10a mice. Our findings revealed that the deletion of Wnt10a decreased neurogenesis, impaired synaptic function, and induced hippocampal neuroinflammation, eventually leading to hippocampal neurodegeneration and memory deficit, possibly through the β-catenin signaling pathway, providing a novel insight into preventive approaches for hippocampus-dependent cognitive impairment.