In pursuing sustainable health solutions and growing demand for neuroprotective interventions, the industry demands alternative green extraction technologies to valorize agri-food by-products. This study aimed to develop an optimized supercritical carbon dioxide extraction to isolate sesame meal’s functional compound (lignans) and assess their neuroprotective effects. Extraction was performed at various pressures (2–4 kpsi), temperatures (40–60 °C), co-solvent concentrations (2–25 mol% ethanol), and CO2 collection segments (0–100 NL) to systematically analyze extraction parameters. Extracts were analyzed quantitatively using high-performance liquid chromatography followed by neuroprotective mechanisms analysis through PC12 neural cell and ischemic stroke models. The results showed that adding ethanol enhanced the polarity and density of supercritical CO2, improving the extraction efficiency of polar lignans. Optimal extraction conditions (4 kpsi, 50 °C, 10 mol% ethanol) yielded the highest sesamol, sesamin, and sesamolin. Extracts showed remarkable protective capabilities when subjected to oxygen–glucose deprivation (OGD) conditions simulating ischemic stress, preventing the enhancement of lactate dehydrogenase activity. Relatively low extract concentrations (25–100 μg/mL) significantly mitigated cellular damage induced by short and extended OGD conditions. The findings revealed green extraction methodologies’ capability to transform sesame meal, a food processing waste, into value-added compounds, in line with sustainable development goals for responsible and sustainable food production, particularly SDGs 3, 9, 12, and 13.
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