The study aimed to design and develop carvedilol loaded silk fibroin-casein nanoparticles using 32 full factorial design. Silk fibroin and casein concentration were selected as the independent variables and their effect were observed on dependent variables: particle size, polydispersity index, encapsulation efficiency, drug release, and dissolution efficiency. The developed optimized formulation was characterized using fourier transform infrared spectroscopy, differential scanning calorimetry, and Powder X-ray diffraction. Surface morphology of optimized formulation using scanning electron microscopy, transmission electron microscopy, and atomic force microscopy revealed spherical nature of particles without any evidence of aggregation. The optimized formulation showed a 2.04-fold increase in Cmax, and 6.87-fold increase in bioavailability as compared to aqueous suspension. The formulation showed sustained release as confirmed by increases in mean residence time. The in vivo in silico simulation using physiologically based pharmacokinetics (PBPK) model and population simulation (100 subjects) revealed a reasonable degree of superimposition of simulated and observed pharmacokinetic parameters based on overall fold error (≤2.0). The enhanced bioavailability with sustained effect demonstrates potential of silk fibroin as an alternative carrier for drug delivery and presents Gastoplus™ as efficient tool for in vivo in silico simulations.