Obesity induces hippocampal neuronal apoptosis and leads to cognitive function deficits. Sonic hedgehog (SHH) signaling is crucial during nervous system development and is neuroprotective in many neurologic diseases. This study assessed the role of SHH signaling in the cognitive deficits in high-fat diet (HFD)-induced obese mice. Flow cytometry assay was used to examine cell apoptosis. Tissue pathology was evaluated by Nissl staining. Immunofluorescent staining and western blotting were used to detect SHH signaling molecules and apoptosis-related proteins. The Morris water maze test was performed to evaluate mouse spatial learning and memory. After HFD feeding for 24 weeks, the expression of SHH signaling molecules was downregulated in the mouse hippocampus. In vitro, GANT61 inhibited SHH signaling and induced apoptosis in HT22 mouse hippocampal cells. Smoothened agonist (SAG), an agonist of SHH signaling, reduced apoptosis in GANT61-treated HT22 cells by regulating caspase-9 and caspase-3 activation. In vivo, 12-week SAG treatment also inhibited the apoptosis of hippocampal neurons in HFD-fed mice by increasing mitofusin 2 (Mfn2) and B-cell lymphoma 2 (Bcl-2) levels and decreasing dynamin-related protein 1 (Drp1) and Bcl-2 homologous antagonist/killer (Bak) levels. Behavioral testing showed that SAG administration ameliorated the cognitive impairment in HFD-fed mice. Downregulation of hippocampal SHH signaling leads to neuronal apoptosis and cognitive deficits in HFD-fed mice. These findings provide useful information for the identification of potential targets for research and therapeutic interventions for cognitive impairment in obesity. Copyright © 2019 Elsevier B.V. All rights reserved.