This study demonstrates the novel application of mixture design in the optimization of biocomposites using mixtures of cocoa pod husk powders (CPHP), tamarind shell powders (TSP), and polylactic acid (PLA). From the experimental results, the hardness value varied between 72.15 ± 3.24 and 79.96 ± 2.52 HRL. Regression and ANOVA analysis indicated significant nonlinear and interaction effects among the components. PLA had the most dominant positive effect, while excessive filler content reduced the biocomposite properties, owing to aggregation and weak interfacial bonding. The optimal formulation of the biocomposite is 5.35 wt% CPHP, 14.65 wt% TSP, and 80.0 wt% PLA with a predicted hardness value of 80.06 HRL. This study offers new perspectives in the optimization of multiple fillers in biocomposite materials, and the effective utilization of waste materials in the development of sustainable materials.