Malignant melanoma (MM) is the most dangerous type of skin cancer with annually increasing incidence and death rates. However, chemotherapy for MM is restricted by low topical drug concentration and multidrug resistance. In order to surmount the limitation and to enhance the therapeutic effect on MM, a new nanoformulation of paclitaxel (PTX)-loaded cholic acid (CA)-functionalized star-shaped poly(lactide-co-glycolide) (PLGA)-D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles (NPs) (shortly PTX-loaded CA-PLGA-TPGS NPs) was fabricated by a modified method of nanoprecipitation. The particle size, zeta potential, morphology, drug release profile, drug encapsulation efficiency, and loading content of PTX-loaded NPs were detected. As shown by confocal laser scanning, NPs loaded with coumarin-6 were internalized by human melanoma cell line A875. The cellular uptake efficiency of CA-PLGA-TPGS NPs was higher than those of PLGA NPs and PLGA-TPGS NPs. The antitumor effects of PTX-loaded NPs were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that star-shaped PTX-loaded CA-PLGA-TPGS NPs were significantly superior to commercial PTX formulation Taxol ®. Such drug delivery nanocarriers are potentially applicable to the improvement of clinical MM therapy.