Herein, lipid-polymer core-shell hybrid nanoparticles composed of poly(D,L-lactic-co-glycolic acid) (PLGA)/lecithin (PLNs) were synthesized through lipid-based surface engineering. Lipids were absorbed onto the surface of the PLGA core to enhance the advantages of polymeric nanoparticles and liposomes. The amounts of lipids and encapsulation of the drug nicardipine hydrochloride (NCH) in the PLNs were studied. NCH-loaded PLNs (NCH-PLNs) were produced in high yield (66%) with a high encapsulation efficiency (92%) and a size of 176 nm. The mass of phosphorus (P) on the NCH-PLN surface was qualitatively and quantitatively investigated using X-ray fluorescence spectroscopy, and lecithin addition increased the P mass percentage due to the phosphate group (PO43-) in its structure. These data confirmed the lipid-based surface engineering of NCH-PLNs. The zeta potential of NCH-PLN exceeded −30 mV, ensuring colloidal stability, and preventing precipitation through electrostatic stabilization. In vitro, NCH was continuously and slowly released from NCH-PLNs over 16 days. Furthermore, PSVK1 cells exhibited high viability after treatment with NCH-PLNs, indicating favorable cytocompatibility. After comparing various mathematical equations of drug release kinetics, the data best fit the Korsmeyer-Peppas model with R2 values of 0.989, 0.990, and 0.982 for 1.0, 3.0, and 5.0 mg/mL lecithin, respectively. The release exponents obtained ranged from 0.480 to 0.505, suggesting anomalous transport release. Thus, NCH-PLNs have potential as a robust drug delivery platform for the controlled administration of NCH, particularly for vasodilation during neurosurgery.