Fast-flow vascular malformations are very difficult to treat by the currently available drug delivery systems due to the particular obstacles associated with rapid blood flow. The goal of the present study is to address such a challenge through a novel chemotherapy approach with the aid of injectable hydrogel. Specifically, a pingyangmycin (PYM)/PECE hydrogel is purposely designed with a programmed synergetic therapy mechanism involving the transient embolotherapy of hydrogel and in situ chemotherapy induced by the locally released drug in a sustained manner. This formulation remained mobile at room temperature whereas rapidly undergoing in vivo sol-gel transition upon injection into the body. The sustained release characteristic of PYM/PECE formulation was revealed both in vitro and in vivo. All the pharmacokinetic characteristics were highly improved including the Tmax, Cmax, t1/2β and AUC(0-t). The exceptional efficacy of PYM/PECE formulation was validated by rapid vascular occlusion in rabbit's fast-flow central auricular arteries whereas respective PYM and PECE treatment failed. The most remarkable features included the precise control over the occlusion site and the irreversible formation of vessel-isolated cell-rich lumps that was believed to benefit the occlusion formation. Intravascular PYM/PECE administration induced neither toxic responses nor histopathological changes in rabbits' major organs. The hydrogel matrix could be completely absorbed in vivo. The present study highlighted the great promise of our design as a safe and extremely effective modality in the treatment of fast-flow vascular malformations.