The aim of this study is to prepare fluvastatin nanostructured lipid carriers (FLV-NLCs) in order to find an innovative way to alleviate FLV-associated disadvantages. The limitations include poor solubility and extensive first-pass metabolism, resulting in low (30%) bioavailability and short elimination half-life (1–3 hours). FLV-NLCs were prepared by hot emulsification–ultrasonication method. Ten runs were created by three-level factorial design (3
2
) to optimize FLV-NLCs formulation process. In this study, two factors, four responses, and three-level factorial design were endorsed. The studied variables were lipid:oil ratio (
X
1
) and sonication time (
X
2
). However, the responses parameter determined the particle size (
Y
1
, nm), entrapment efficiency percent (EE%,
Y
2
), particles zeta potential (
Y
3
), and 80% of the drug release after 24 hours (
X
4
). Furthermore, stability and in vivo pharmacokinetics were studied in rats. The optimized consisted formula had an average particle size of 165 nm with 75.32% entrapment efficiency and 85.32% of drug released after 24 hours, demonstrating a sustaining drug release over 24 hours. An in vivo pharmacokinetic study revealed enhanced bioavailability by >2.64-fold, and the mean residence time was longer than that of FLV. We concluded that NLCs could be promising carriers for sustained/prolonged FLV release with enhanced oral bioavailability.