Tumor metastasis has become a key obstacle to cancer treatment, which causes high mortality. Nowadays, it involves multiple complex pathways, and conventional treatments are not effective due to fewer targets. The aims of the present study were to construct a novel liposome delivery system co-loading a specific PLD inhibitor 5-fluoro-2-indolyldes-chlorohalopemide (FIPI) in combination with antitumor drug doxorubicin (DOX) and functional excipient D-alpha tocopheryl acid succinate (α-TOS) for anti-metastasis. In this study, the liposomes containing three components (DFT-Lip) with different physicochemical properties were successfully prepared by film dispersion method combined with pH-gradient method. Physicochemical parameters such as particles size, potential, encapsulation efficiency, stability, and release profiles were investigated. In vitro and in vivo anti-metastasis effectiveness against highly metastatic breast cancer MDA-MB-231 cell line was evaluated. The liposomes showed uniform particle size (approximately 119 nm), high drug encapsulation efficiency (> 90%), slow release characteristics and stability. In vitro anti-tumor cell metastasis study demonstrated DFT-Lip could greatly inhibit motility, migration and invasion of MDA-MB-231 cells compared to other liposomes, predicting a synergistic anti-tumor metastasis effect between FIPI with α-TOS in liposomes. In vivo anti-metastasis study showed that DFT-Lip prevented the initiation and the progression of metastasis of high metastatic breast cancer. These results suggested that the liposomes containing DOX, FIPI, and α-TOS might be a promising strategy for metastatic tumor therapy in clinics.