Cefixime is BCS class 2/4 drug whose oral absorption is limited by its solubility and/or permeability. The use of HPBCD is proved to be better complexing agent for enhancing solubility as well as permeability of drugs. At the same time spray drying is the one step continuous drying process making it attractive technique for industrial application. Therefore, the current study was undertaken to unite the use of HPBCD and spray drying alongside with optimizing it through Design of Experiments (DOE) approach by means of Box–Behnken design for the benefit of drugs like Cefixime that needs to be redeveloped for better therapeutic efficacy. These formulations were evaluated by solubility studies, process yield and total drug content with help of independent variables like air inlet temperature, aspirator rate and pump feed rate. The optimized formulation was also characterized by SEM, FTIR analysis and in vitro dissolution study. Inlet air temperature was found to be the most important parameter for the spray dried material characteristics, followed by the aspirator flow rate whereas Feed flow rate was found less significant. The results indicate that formulation parameters are at least important than process parameters when designing a proper process for spray drying inclusion complex. The optimized formulation was also then compressed into tablet and was compared with marketed formulation where it showed comparable dissolution.