Melanoma, the most malignant form of skin cancer, shows resistance to traditional anticancer drugs including paclitaxel (PTX). Furthermore, over 50% of melanoma cases express the BRAF^V600E mutation which activates the MAPK pathway increasing cell proliferation and survival. In the current study, we investigated the capacity of the combination therapy of PTX and the MAPK inhibitor, PD98059, to enhance the cytotoxicity of PTX against melanoma and therefore improve treatment outcomes. Synergistic in vitro cytotoxicity was observed when soluble PTX and PD98059 were used to treat the A375 melanoma cell line as evidenced by a significant reduction in the cell viability and IC₅₀ value for PTX. Then, in further studies, TPGS-emulsified PD98059-loaded PLGA nanoparticles (NPs) were prepared, characterized in vitro and assessed for therapeutic efficacy when used in combination with soluble PTX. The average particle size (180 nm d.), zeta potential (−34.8 mV), polydispersity index (0.081), encapsulation efficiency (20%), particle yield (90.8%), and drug loading (6.633 µg/mg) of the prepared NPs were evaluated. Also, cellular uptake and in vitro cytotoxicity studies were performed with these PD98059-loaded NPs and compared to soluble PD98059. The PD98059-loaded NPs were superior to soluble PD98059 in terms of both cellular uptake and in vitro cytotoxicity in A375 cells. In in vivo studies, using A375 challenged mice, we report improved survival in mice treated with soluble PTX and PD98059-loaded NPs. Our findings suggest the potential for using this combinatorial therapy in the management of patients with metastatic melanoma harboring the BRAF mutation as a means to improve survival outcomes.