Melanoma is one of the most aggressive types of cancer and is prone to metastasis, making current clinical treatment quite difficult. The usage of the first-line medication dacarbazine (DTIC) for melanoma is limited due to harsh side effects, limited water solubility, and a short half-life. To tackle these disadvantages, polylactic acid-hydroxyacetic acid copolymer nanoparticles (NPs) loaded with dacarbazine and ursolic acid (NPs) were fabricated, which were further encapsulated with a red blood cell membrane (RNPs). MTT, apoptosis assay, wound healing assay, colony formation assay, and immunohistochemistry were used to assess the antitumor effect of NPs and RNPs. Ferroptosis evaluation was implemented using GSH detection and the malondialdehyde assay. We found that RNPs exhibited stability and biosafety in vitro and in vivo and achieved superior anticancer ability against xenograft tumors compared with single agents and NPs, which indicated the synergistic and biomimetic efficacy. Furthermore, ferroptotic activity was observed in RNPs-treated tumor cells, and ferroptosis inhibition could partially rescue melanoma cells from RNPs-induced cell death. Collectively, this study evaluated the potential of RNPs as a novel biomimetic nanomedicine for synergistic melanoma therapy by eliciting ferroptosis in tumor cells with both anticancer activity and biosafety.