Rosuvastatin calcium (Rsv) is one of the most recent and effective statins, with a potent antihyperlipidemic effect. However; it suffers poor bioavailability owing to its poor solubility. Thus; encapsulating Rsv into a nanovesicular structure could overcome this problem. The aim of this work is to investigate the potential of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in enhancing the solubility of Rsv, using Quality by Design (QbD) concept to develop a better quality product. A complete risk assessment study has been conducted, where the critical process parameters (CPP), material attributes (MA), and critical quality attributes have been identified using the ishikawa diagrams. Selected CPP/MA were screened and further upgraded to a 2⁴ full factorial design to develop the design space with the optimized formula. The screened CPP/MA were tested on each of the particle size, polydispersity index (PDI), zeta potential and the entrapment efficiency (EE%). A comprehensive approach for Rsv nanovesicular carriers has been conducted, where the NLC showed better results than the SLN. The optimized formula was prepared with 3 % total lipid content, 0.154% surfactant, and 9.4 mg drug. The optimized formula had a particle size 310.5 nm, with 0.243 PDI, a zeta potential of -24.7 mV and EE% of 93.87%, and showed a sustained release of the drug up to 72 hours. It successfully lowered each of the total cholesterol, low density lipoprotein, and triglycerides and elevated the level of the high density lipoprotein of high fat fructose diet-induced hyperlipidemia/hypercholesterolemia rats, with better results as compared to the standard drug. Thus, a complete QbD study was conducted to explore experimental regions for many successful nanovesicular carriers for the enhancement of the solubility of poorly soluble drugs.