We report here a catalytically active nano covalent organic framework [COF(Fe)] with high drug loading capacity for reversing tumor multidrug resistance (MDR). The Fe catalytic sites in COF(Fe) could convert intracellular overexpressed H2O2 into highly reactive ˙OH to induce oxidation stress and down-regulate MDR protein. Therefore, COF(Fe) could enhance the intracellular drug accumulation to overcome MDR, which was demonstrated both in vitro and in vivo.