Bacillus amyloliquefaciens BLB369 is an important plant growth-promoting bacterium, which produces antifungal compounds. A statistics-based experimental design was used to optimize a liquid culture medium using inexpensive substrates for increasing its antifungal activity. A Plackett–Burman design was first applied to elucidate medium components having significant effects on antifungal production. Then the steepest ascent method was employed to approach the experimental design space, followed by an application of central composite design. Three factors were retained (candy waste, peptone, and sodium chloride), and polynomial and original trigonometric models fitted the antifungal activity. The trigonometric model ensured a better fit. The contour and surface plots showed concentric increasing levels pointing out an optimized activity. Hence, the polynomial and trigonometric models showed a maximal antifungal activity of 251.9 (AU/mL) and 255.5 (AU/mL) for (19.17, 19.88, 3.75) (g/L) and (19.61, 20, 3.7) (g/L) of candy waste, peptone, and NaCl, respectively. This study provides a potential strategy for improving the fermentation of B. amyloliquefaciens BLB369 in low-cost media for large-scale industrial production.