The invention discloses a targeting drug delivery system capable of resisting drug-resistant tumor and a preparation method of the targeting drug delivery system. The targeting drug delivery system isa nano-micelle taking a polyethylenimine-alpha-tocopheryl succinate polymer as a drug delivery core and a quercetin-modified hyaluronic acid polymer as a shell. Experiments prove that the targeting drug delivery system has certain acid sensitivity, can be actively released in a tumor microenvironment, is quickly diluted by blood after entering blood, cannot cause severe hemolysis, has higher safety, is applicable to intravenous injection administration, can reverse drug resistance of drug-resistant tumor cells to a certain degree, can significantly improve sensitivity of drug-resistant tumorcells to chemotherapy drugs, can increase accumulation of chemotherapy drugs at tumor parts, can remarkably improve treatment effects of the chemotherapy drugs on drug-resistant tumor, has good tumortargeting functions and has no obvious toxic or side effects; and besides, the preparation is easy to realize, simple to operate and good in repeatability.