Metastasis is a key factor that limits survival in the majority of patients with cancer. Thus, numerous efforts have been made to elucidate the molecular mechanisms involved in this phenomenon. B16‑F10 melanoma cells have been demonstrated to be highly metastatic to the lungs in mice. The aim of the current study was to investigate the role of CXC motif chemokine receptor 4 (CXCR4) in the metastatic potential of B16‑F10 melanoma cells in mice. In vitro transfection of B16‑F10 tumor cells with CXCR4 short hairpin RNA (shRNA) expressing plasmids (CXCR4 shRNA) significantly reduced the expression levels of CXCR4 mRNA (80%) and protein (68%), compared with the control. In addition, these results demonstrated that pulmonary metastasis was significantly inhibited (85%) in mice inoculated with CXCR4 shRNA‑transfected B16‑F10 melanoma cells. The polycation‑based nanoparticle (jetPEI) was used to investigate the effect of CXCR4 knockdown in vivo on the metastatic potential of B16‑F10 melanoma cells. The number of pulmonary metastatic nodules was significantly reduced (50%) in animals that received a retro‑orbital injection of jetPEI‑CXCR4‑1 shRNA. The current study demonstrated that CXCR4 serves a role in the metastatic potential of B16‑F10 melanoma cells. Currently there is a great interest in the development of antagonists for the therapeutic targeting of CXCR4 expression. Taking the results of the current study and the fact that CXCR4 is highly conserved between humans and mice into account, this experimental model of metastasis with B16‑F10 melanoma cells may aid in the discovery of CXCR4 antagonists with clinical implications.