Liver cancer is a major global health challenge, ranking as the third leading cause of cancer-related deaths worldwide. In this study, we explore the use of paclitaxel-coated ZIF-8 metal-organic framework nanoparticles (ZIF-8 NPs/Pacx) as a novel drug delivery system for enhanced liver cancer treatment. A comprehensive set of analyses, including morphology evaluation, particle size distribution, zeta potential measurement, drug loading capacity, encapsulation efficiency, stability, and In vitro drug release behavior, was conducted to assess the nanoparticles’ performance. The ZIF-8 NPs/Pacx demonstrated significant antitumor activity at a concentration of 75 µg/mL, particularly against HepG2 and Hep3B liver cancer cell lines. RT-PCR analysis revealed that ZIF-8 NPs/Pacx stimulated TNF-α expression in HepG2, Hep3B, and normal liver cells (NLCs), with further confirmation through Western blot analysis of TNF-α and β-actin levels. Notably, the nanoparticles exhibited the ability to inhibit cell proliferation and induce apoptosis in liver cancer cells. These findings suggest that ZIF-8 NPs/Pacx could offer an innovative approach for the delivery of paclitaxel to liver cancer cells, maximising treatment effectiveness with minimal side effects, and positioning this system as a promising candidate for future liver cancer treatments.