In this study, we presented a novel hybrid perfusion mode in an attempt to provide a new strategy to improve the survival of an extended large flap and discuss its possible mechanisms. A 14 × 10 cm flap was designed on the rabbit abdomen. Ninety-six rabbits were randomly divided into three groups based on the flap perfusion mode: control group I (CON 1, physiological perfusion mode with bilateral deep inferior epigastric vascular pedicles intact), control group II (CON 2, physiological perfusion mode with single deep inferior epigastric vascular pedicle intact), hybrid nourished group (physiological perfusion as in CON 2 combined with arterialized venous nonphysiological perfusion mode, referred to as a hybrid perfusion mode). Flap survival, status of vascular perfusion, microvasculature, histopathology, expression of CD34, eNOs, VEGF and metabolic status of the flaps by LC-MS were assessed in each group. The results of “hybrid nourished” flaps were similar to the traditional flaps in terms of flap survival, level of vascular perfusion and microvasculature except the status of metabolites. The feasibility of this novel hybrid perfusion mode will greatly extend the indications of flap transfer and efficiently improve the survival reliability of large flaps. In a sense, this mode will be an ideological emancipation for the field of flap surgery.