Acute ischemic stroke is a leading cause of disability and death. The development of neuroprotectants is an emerging strategy for the treatment of ischemic stroke. In this work, we designed and synthesized a series of 1,3,5-triaryl substituent triazole derivatives by introducing a phenolic group and phenyl ring to 3,5-diaryl substituents oxadiazole. Structure-activity relationship (SAR) analysis showed that compounds with alkyl groups or with substituents at the 3-position possessed better protective effects. Among the derivatives, 3,5-dimethyl substituted compound 24 exhibited the best neuroprotective effect with weak cytotoxicity. Compound 24 possessed a high plasma protein binding rate, moderate hERG inhibition, low acute toxicity, and suitable pharmacokinetic properties. In vivo experiments demonstrated that compound 24 exerted a protective effect by reducing cerebral infarction size, improving neurological behavior, and restoring redox balance in middle cerebral artery occlusion rats. Further investigation indicated that compound 24 exerted a protective effect against sodium nitroprusside (SNP) induced cell damage by scavenging intracellular reactive oxygen species and restoring mitochondrial membrane potential. Moreover, compound 24 induced the nuclear translocation of Nuclear factor erythroid 2-related factor (Nrf2) and promoted the generation of antioxidative proteins, including Heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase (NQO1), and glutamate-cysteine ligase catalytic (GCLC). Surface plasmon resonance (SPR) experiments indicated that compound 24 might activate the Nrf2 signaling pathway by interacting with the Keap1 Kelch domain. Taken together, these facts indicate that compound 24 might have potential in the treatment of ischemic stroke.