Based on the scaffold of edaravone, a clinically approved neuroprotective agent, a series of edaravone/benzocyclopentenone hybrid derivatives were designed, synthesized and evaluated for their biological activities in vitro and in vivo. Most of the compounds demonstrated promising neuroprotective effects, with derivatives containing benzofuranone or indanone as core moiety showing particularly strong activity. Among all derivatives, 17 compounds exhibited significantly improved neuronal cell viabilities compared to edaravone in an OGD/R model with rat primary neuronal cells, along with favorable safety profiles and blood-brain barrier permeability. Notably, compound 13, which includes a fluoro-substituted benzofuranone fragment, displayed the most potent neuroprotective effect in vitro and effectively reduced cerebral infarct area in vivo.