Repaglinide (REP) is a potent medication for treating diabetes (BCS class II) that has a low oral bioavailability of less than 55% due to its poor solubility and significant metabolism in the liver during its first pass. The objective of this study was to develop a nanocarrier system called nanostructured lipid carriers loaded with repaglinide (REP-NLCs) that provides the benefits of prolonged drug release and enhanced oral bioavailability. Conducting solubility experiments allowed for the identification of suitable lipids and surfactants for the formulation of NLCs. The REP-NLCs were synthesized using hot homogenization followed by ultrasonication procedures and subsequently analyzed for their size, zeta potential, polydispersity index (PDI), and drug entrapment efficiency (E.E). The results demonstrated that altering the lipid or surfactant type had a significant impact on the entrapment efficiencies, particle size, and release behavior of the NLCs. The average particle size varied between 59.1 ± 3.2 and 898.4 ± 40.3 nm. The particles exhibited a negative charge, with zeta potential values ranging from −32.27 ± 1.01 to −26.13 ± 7.37 mV. The in vitro release of all REP-NLC formulas exhibited a biphasic time-dependent pattern. The E.E varied between 70.11 ± 5.3 and 85.32 ± 4.6 %. REP-NLCs exhibited prolonged drug release compared to the dissolution of REP suspension.