Although chemotherapy regimens are well-established in clinical practice, chemoresistance and adverse side effects pose significant obstacles in cancer treatment. Paclitaxel (PTX), a widely used chemotherapeutic agent, faces formulation challenges due to its poor solubility and permeability. Research suggests that the phytochemical Cannabidiol (CBD) holds potential not only in targeting cancer cells but also in alleviating pain and nausea, thereby improving the quality of life for cancer patients. However, CBD's clinical application is also limited by its poor solubility, low bioavailability, and susceptibility to oxidation. Nanostructured lipid carriers (NLCs) represent a promising drug delivery system for hydrophobic compounds like PTX and CBD and allow their coencapsulation. Nonetheless, achieving a stable formulation requires the identification of suitable preparation methods and excipients. The aim of this study was to develop and optimize an NLC formulation for the coencapsulation of PTX and CBD. Using factorial design, an optimized formulation was obtained with homogeneous particle sizes (200 nm), negative ZPs (-16.1 mV), a particle concentration of 10 particles/mL, spherical morphology (TEM images), and a lipid core with low crystallinity (confirmed by XRD). To evaluate the therapeutic potential of the drug combination, cell viability assays were conducted on murine melanoma cells (B16-F10) at different exposure times (24 and 48 h). The NLC-CBD-PTX formulation significantly reduced cell viability in a time- and concentration-dependent manner, demonstrating at least 75% greater activity at 24 h compared to each drug individually, whether free (PTX, CBD) or encapsulated (NLC-PTX, NLC-CBD). This indicates a synergistic effect between CBD and PTX when coencapsulated, particularly at higher concentrations and shorter exposure times. In conclusion, an innovative pharmaceutical formulation coencapsulating PTX and CBD was validated, showing potential to enhance antitumor efficacy, overcome chemoresistance, reduce side effects, and broaden therapeutic applications. The resulting NLCs exhibited favorable physicochemical properties, supporting their suitability for various routes of administration.