The development of sustainable drug delivery systems is very important in the field of pharmaceutical research and has many advantages over the usual methods of drug administration, including improving effectiveness, reducing side effects, and increasing patient compliance. Among various techniques, electrospraying as a voltage‐driven process has emerged as a promising technology for the fabrication of drug‐loaded nanoparticles. In recent years, the application of electrospray approach for drug release has been widely investigated. However, optimization of electrospray process parameters and development of mathematical models to predict drug release kinetics from microparticles are still challenging. To address these issues, a combination of Central Composite Design (CCD) and Response Surface Methodology (RSM) has been used. This paper focuses on the application of CCD‐RSM for modeling and optimization of doxorubicin (DOX)‐poly(caprolactone) (PCL)‐polyethylene glycol (PEG) microparticles prepared using electrospray method. Doxorubicin, a widely used anticancer drug, exhibits potent cytotoxicity against a wide range of cancers. PCL‐PEG microparticles are promising as drug carriers due to their biocompatibility, controlled release properties, and ability to protect the encapsulated drug from degradation. The CCD‐RSM approach allows systematic investigation and optimization of several formulation and process variables, including polymer concentration, PCL‐PEG weight ratio, and applied voltage on drug release behavior. In addition, the effect of rheology and electrical conductivity of polymer fluid on the size of particles obtained from electrospraying was investigated. The effect of adding folic acid and doxorubicin in the optimized sample of nanoparticles and the effect of different concentrations of doxorubicin were investigated, and SEM, DLS, and FTIR techniques were used to characterize the microparticles, and the MMT test was performed to evaluate their cytotoxicity. The results showed that the optimized formulation is effective for sustained drug release over a long period for drug delivery applications.