Paclitaxel (PTX) is widely used as a radiosensitizer in the clinical treatment of cancer. However, the efficacy of chemoradiotherapy is limited by the hostility of the tumor microenvironment such as hypoxia. To overcome this constraint, we designed pleiotropic radiotherapy sensitized liposomes containing perfluorotributylamine (PFTBA) and PTX. The results showed that liposomes significantly accumulated in the tumor site. PFTBA in liposomes dramatically reversed tumor hypoxia and improved the sensitivity of tumor radiotherapy. PTX in liposomes blocked the cell cycle of tumor cells in the radiation-sensitive G2/M phase, which was even greater when combined with PFTBA. In vitro and in vivo tumor treatment further demonstrated remarkably improved therapeutic outcomes in radiotherapy with such biocompatible liposomes. In conclusion, the pleiotropic liposomes encapsulated PFTBA and PTX provide significant radiotherapy sensitization and show promise for future application in clinical medicine.