Background/Objectives: Hepatocellular carcinoma, or liver cancer, is the sixth most common cancer worldwide and the third leading cause of cancer-related mortality. Therefore, this study aimed to develop and optimise etodolac-loaded sodium deoxycholate-stabilised shellac-based polymeric nanoparticles (ETD-SDS-SHNPs) to improve the pharmacokinetic profile of etodolac (ETD) in HepG2 human hepatocellular carcinoma (HCC) cells. Methods: The nanoprecipitation method was used to prepare ETD-SDS-SHNPs, which were then optimised using a Box–Behnken design and evaluated for particle size (PS), zeta potential (ZP), entrapment efficiency (EE), solid-state characterization, and in vitro drug dissolution. Furthermore, in vivo oral bioavailability, cytotoxicity, cellular uptake, and cell cycle progression were assessed. Results: The optimised ETD-SDS-SHNPs formulation showed an average PS of 192 ± 1.50 nm, ZP of −20.2 ± 0.4 mV, and EE of 81.6 ± 1.42%. Differential scanning calorimetry and X-ray diffraction confirmed the reduced crystallinity of ETD-SDS-SHNPs, indicating partial amorphisation of the drug in the formulation. Field-emission scanning electron microscopy revealed predominantly spherical nanoparticles with relatively smooth surfaces. The peak plasma concentration (C_max) of ETD-SDS-SHNPs (11.86 ± 0.12 µg/mL) was significantly higher than that of the pure ETD (7.15 ± 0.14 µg/mL). Similarly, the AUC_0–t for ETD-SDS-SHNPs (351.63 ± 4.59 µg·h/mL) was approximately 1.48-fold greater than that of the pure drug (236.09 ± 4.60 µg·h/mL), indicating enhanced bioavailability. ETD-SDS-SHNPs demonstrated dose-dependent enhancement of cytotoxicity against HepG2 cells, accompanied by S-phase cell cycle arrest and increased cellular uptake. Conclusions: ETD-SDS-SHNPs formulation offers an enhanced passive, efficient, and safer nanocarrier platform for repurposing etodolac in liver cancer therapy, showing significant promise for improving clinical outcomes in HCC treatment.