Purpose: To assess the effect of the lactic acid (LA)-to-glycolic acid (GA) molar ratio and polyethylene glycol (PEG) concentration on the formation of poly-lactide co-glycolide acid (PLGA)-PEG-PLGA co-block polymers simultaneously using statistical approach. Methods: A 22 full factorial design with the addition of a point in the center of the design, namely curvature, was applied. Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR) were performed to confirm the formation of the co-block polymer. Simvastatin (SMV), a drug model was incorporated into the nano-polymeric micellar (NpM) of PLGA-PEG-PLGA followed by solubility phase, particle size, zeta potential, and entrapment efficiency characterizations. Results: FTIR, DSC, and NMR successfully confirmed the formation of co-block polymers. Solubility of SMV increased from 2 to 44-folds depending on co-block concentration with entrapment efficiency of 59%-80%. The NpM had size in the range of 206 to 402 nm with negative zeta potential. LA to GA ratio had greater effect on particle size reduction and increasing of co-polymer length. In addition, it had higher contributions on increasing of solubility and entrapment efficiency of SMV than PEG. Conclusion: According to these findings, the LA to GA ratio and PEG concentration gained a great consideration in order to prepare the PLGA-PEG-PLGA co-block which fulfilled the quality target product profile of NpM delivery system.