In this study, biodiesel, also known as fatty acid methyl ester (FAME), was synthesized from multi-stage frying waste soybean oil using chicken eggshell-derived CaO and potassium-impregnated K+-CaO heterogeneous catalysts. Potassium-impregnated catalysts (1.25% K+-CaO, 2.5% K+-CaO, and 5% K+-CaO) were developed by treating the calcined waste eggshell powder with KOH in different wt % ratios. The catalysts were characterized using FTIR, XRD, FESEM, EDS, BET, and particle size analysis techniques. Box-Behnken design-based optimization was exploited to optimize the reaction parameters. A maximum yield of 98.46%, calculated via 1H NMR, was achieved following a 5% K+ doping, 12:1 methanol to oil molar ratio, 3% catalyst amount, 180 min reaction time, and 65 °C reaction temperature. The catalyst (5% K+-CaO) responsible for maximum biodiesel production was found to be highly reusable, with a 30.42% conversion decrease in activity after eight cycles of reuse. Gas chromatography was used to determine the composition of FAME produced from different cycles of waste soybean oil. Physicochemical parameters of the synthesized biodiesel were found to be compatible with EN and ASTM standards. This study has shown that the waste eggshell-derived heterogeneous catalysts have significant catalytic activity at relatively low K+ doping and catalyst loading leading to high biodiesel conversion.