Objective To investigate the effects of microRNA (miR)-17-5p regulation of the hypoxia-inducible factor-1α (HIF-1α)/Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) pathway on cognitive function and hippocampal synaptic plasticity in epileptic mice. Methods A mouse epilepsy model was established by intraperitoneal injection of pentylenetetrazol (PTZ). Specific pathogen-free BALB/c mice were randomly assigned to seven groups (n=12 each): normal control, PTZ, miR‑17‑5p agomir control (PTZ + agomir negative control), miR‑17‑5p agomir (PTZ + miR‑17‑5p agomir), miR‑17‑5p agomir + pcDNA (PTZ + miR‑17‑5p agomir + empty vector), miR‑17‑5p agomir + pc-HIF‑1α (PTZ + miR‑17‑5p agomir + HIF‑1α overexpression plasmid), and miR‑17‑5p agomir + pc-BNIP3 (PTZ + miR‑17‑5p agomir + BNIP3 overexpression plasmid). Cognitive function was evaluated by the Morris water maze test. Field potential recording was used to measure field excitatory postsynaptic potentials (fEPSPs) in the hippocampal CA1 region. Transmission electron microscopy was used to observe synaptic ultrastructure. Quantitative real-time reverse transcription polymerase chain reaction and Western blot were employed to detect miR‑17‑5p, HIF‑1α, BNIP3, and synapse-related proteins [postsynaptic density protein 95 (PSD95), synaptotagmin-1 (Syt1), synaptosome-associated protein 25 (SNAP25), and gephyrin] in the hippocampus. A dual-luciferase reporter assay was used to verify whether miR-17-5p directly targets HIF-1α. Results Compared with the normal control group, the PTZ group showed significant cognitive impairment (prolonged escape latency, reduced time in the target quadrant, and fewer platform crossings), damage to hippocampal synaptic structure (widened synaptic cleft and thinner postsynaptic density), reduced synaptic plasticity (a decreased maximum amplitude of fEPSPs and a reduced increase in the fEPSP slope 1 hour after high-frequency stimulation), downregulation of miR‑17‑5p and synapse-related proteins (PSD95, Syt1, SNAP25, and gephyrin), and upregulation of HIF‑1α and BNIP3 (P<0.05). In the miR-17-5p agomir group, these pathological changes were significantly reversed compared with the PTZ group (P<0.05). Overexpression of HIF‑1α or BNIP3 antagonized the protective effects of miR‑17‑5p, restoring all indicators except miR-17-5p to levels close to those of the PTZ group (P<0.05). The dual-luciferase assay confirmed that miR‑17‑5p could directly bind to the 3′-UTR of HIF‑1α. Conclusions miR‑17‑5p can directly target and inhibit the HIF‑1α/BNIP3 pathway, upregulate the expression of synapse-related proteins, repair hippocampal synaptic ultrastructure, enhance synaptic plasticity, and thereby improve cognitive function in epileptic mice, providing a potential therapeutic target for epilepsy-related cognitive impairment.