Lung cancer is the second most common type of cancer and the leading cause of cancer-related deaths worldwide. Some chemotherapeutic agents, such as curcumin and gemcitabine, have low bioavailability due to their hydrophobicity or the need for specialized transporters. This limits their cytotoxic potential against tumor cells but can be addressed through nanoencapsulation. This study evaluated the effects of nanometric encapsulation of curcumin and gemcitabine in chitosan, a biocompatible polymer, on the A549 lung cancer cell line and B16F10 murine melanoma cells. The chemical properties of the synthesized nanoparticles were characterized using UV-vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM). The nanoparticles ranged in size from 180 to 197 nm, with a positive surface charge between 11.8 and 16.3 mV. Cytotoxicity assays were conducted on the A549 and B16F10 cell lines, along with morphological analyses of apoptosis and flow cytometry to assess cell death mechanisms. Compared to the free drugs, the nanometric encapsulation of curcumin and gemcitabine did not always enhance the cytotoxic effects, but it did induce pronounced apoptosis in the lung cancer cells. These findings suggest that this approach could optimize drug delivery, reduce the required doses, and minimize side effects, thereby improving the overall efficacy of lung cancer treatment.