Cancer, a prevalent global health issue, is commonly treated with surgery, chemotherapy, radiation therapy, and hormonal therapy, often resulting in severe side effects and recurrence. The advent of nanoparticles has revolutionized drug delivery by enhancing the antitumor therapy efficacy and overcoming multidrug resistance. These nanocarriers encapsulate drugs, enabling targeted delivery and mitigating the limitations of pure drug forms. Polymeric nanoparticles (PNPs) have gained significant interest due to their small size, controlled drug release, and high stability. Similarly, lipid-based nanocarriers offer comparable benefits but face challenges such as structural instability and short circulation time. To address these limitations, polymer-lipid hybrid nanoparticles (PLNs) have been developed, combining the advantages of both polymeric and lipid-based systems. Various polymers such as polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), polycaprolactone (PCL), poly(vinyl alcohol) (PVA) chitosan and hyaluronic acid along with natural and synthetic phospholipids, are utilized in PLN fabrication. Surface functionalization using aptamer, antibodies, ligands, and PEGylation enhances the cancer-targeting properties of these nanoparticles. The drug release mechanism of PLNs involves diffusion across the lipid bilayer and erosion of the polymer core, influenced by factors such as drug solubility, polymer-drug interactions, polymer degradation rate, and particle size. This chapter discusses the types and fabrication processes of PLNs, the polymers and lipids used, surface functionalization, drug release mechanisms, and their biomedical applications in cancer treatment.