Fresh Ginkgo biloba seeds (GBS) contain rich bioactive compounds; nevertheless, it is slightly poisonous and cannot be eaten directly due to higher Ginkgotoxin and ginkgolic acid. Though drying can lower the Ginkgotoxin and ginkgolic acid contents, it can also have an adverse effect on the bioactivity and product quality. Infrared drying offers lower drying time, high energy savings, and product quality; therefore, optimizing the process parameters for multiple responses is paramount. In this study, Plackett–Burman Design (PBD)–Response Surface Methodology was systematically used to optimize GBS's infrared-drying parameters. Screening of factors by PBD indicated temperature, time, and height contributed significantly to moisture content (MC), total colour change (Δ E ), total phenolic content (TPC), and Ginkgotoxin (MPN). Further using rotatable central-composite design to obtain the optimum conditions were temperature (80 °C), time (159.68 min), and height (12 cm). Satisfactory results were (6.09 ± 0.15)%, 5.56 ± 0.45, (6.25 ± 0.38) mg gallic acid equivalent/g, and (50.57 ± 1.10) μg/g for MC, Δ E , TPC, and MPN, respectively, with verification close to the predicted values. This shows an increase in TPC, appreciable Δ E , MC, and a drastic reduction in MPN (5.45 fold) compared with fresh GBS. The quality assessment showed higher pyridoxine , anti-oxidant activities and total flavonoid , lower enzyme activity and ginkgolic acid (10 fold), granular adhesion (from the micrograph), and satisfactory product quality. This shows the infrared-dried GBS under these optimum conditions had ginkgotoxin and ginkgolic acid contents that are below the level likely to cause toxicity, thus could be useful for food and industrial production as a functional food and neutraceutical.