Although microwave (MW) thermal therapy has been widely studied for the treatment of tumors due to its less invasiveness, the recurrence of tumors is still observed because of the relatively low bioavailability of MW sensitizers. For enhancing the bioavailability of MW sensitizers, triphenyl phosphate (TPP)-conjugated and doxorubicin (DOX)-loaded porous zirconium metal-organic framework nanocubes (ZrMOF NCs) modified by polyethylene glycol (PEG), ZrMOF-PEG-TPP@DOX NCs, are prepared as the MW sensitizer with mitochondria target. Moreover, the mitochondria are more susceptible to heat than tumor tissues, causing the improvement of tumor cell apoptosis. Our results show that ZrMOF NCs exhibit excellent heating effects due to the increased collisions of the ions in the ZrMOFs’ micropores under MW irradiation. ZrMOF-PEG-TPP@DOX NCs behave preferential aggregation at the mitochondria confirmed by confocal microscopy images. In vivo MW thermal therapeutic efficacy of ZrMOF-PEG-TPP@DOX NCs + MW is also better without recurrence during treatment than that of ZrMOF-PEG@DOX NCs + MW at the similar thermal therapeutic temperature, revealing that the mitochondria targeting strategy can enhance MW thermal therapeutic efficacy. This work provides a new biosafety MW sensitizer with mitochondria target for enhancing MW thermal therapy against tumors.