Combinations of natural bee wax flavones chrysin with a chemo drug have been exhibiting high potential with reduced adverse effect. To extend the synergistic effect of chrysin and improve the MLNPs (Multi Layer Nanoparticles) performance in drug release, layer-by-layer of poly [di(sodium carboxyphenoxy)phosphazene] (PDCPP) and poly (diallyldimethyl ammonium chloride) (PDADMAC) deposited on the CaCO₃ nanoparticles (CCNPs) surface. The results suggest spherical MLNPs of 237 nm are formed with high drug loading content with enhanced cellular uptake. Under acidic conditions, multi layer structure effectively controls burst release, providing sustained drug release for long period. The combined effect of chrysin and cisplatin improved the cytotoxic potential of MLNPs at 25 μg.mL⁻¹ concentration. Angiogenesis inhibitor chrysin activates reactive oxygen species (ROS) production and eventually leads to mitochondrial dysfunction. Furthermore, significant decreases of buccal pouch carcinoma in hamster model. Dual drug loaded MLNPs achieves 92% regressions of tumor volume as compared to cisplatin alone loaded MLNPs. In addition, Histopathology studies demonstrated the biocompatible effect of MLNPs on vital organs. This work provides a simple method to formulate multiple drugs in single nanosystem with high therapeutic efficacy on oral cancer.