This study aimed to evaluate the efficacy of puerarin and its effect on synaptic plasticity in rats with focal cerebral ischemia (FCI) by modulating the silent mating type information regulation 2 homolog (SIRT1)/hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway. Fifty specific pathogen-free-grade healthy male rats were randomly divided into sham operation group (SOG), model group, low-dose group, medium-dose group, and high-dose group, with 10 rats in each group. The SOG group received sham operation and saline treatment, while the other four groups received the same amount of saline, 25 mg/kg, 50 mg/kg, and 100 mg/kg of puerarin injection, respectively. After modeling, the rats exhibited higher neurological deficit, inflammation, cerebral infarction rate, and lower forelimb motor function as well as lower protein expressions of SIRT1, HIF-1α, VEGF, synaptophysin (SYN), and postsynaptic density protein (PSD)-95. With the treatment of different doses of puerarin, the degree of neurological impairment, impaired motor function, cerebral infarction rate, and the levels of inflammatory factors (interleukin [IL]-1β, IL-6, and intercellular adhesion molecule 1) in brain tissues were reduced; the protein expressions of SIRT1, HIF-1α, VEGF, SYN, and PSD-95 in brain tissues were enhanced, and the synaptic volume density, numerical density, surface density, width of synaptic cleft, and curvature of the synaptic interface in the cerebral cortex were also improved. Notably, the effects of puerarin on the above-mentioned indicators were dose-dependent. Puerarin can improve neurological impairment and forelimb motor function, reduce inflammatory response, inhibit brain edema, regulate synaptic plasticity, and restore the curvature of synaptic interface in rats with FCI, and its mechanism of action may be related to the activation of SIRT1/HIF-1α/VEGF signaling pathway.