Quinone oxidoreductase isozyme I (NQO1) is a cytoprotective two-electron-specific reductase that highly expresses in various cancer cells. Taking NQO1 as the target, we herein report three hybrid compounds from Pt(IV) complexes and a quinone propionic acid unit. The mechanism studies showed that the hybrids could be activated by both NQO1 and ascorbic acid to release the cytotoxic Pt(II) unit, exhibiting a dual stimuli-responsive character. In the pharmacological studies, complexes 2 and 3 presented higher antitumor activity than cisplatin. More importantly, the hybrid could also overcome cisplatin resistance due to the NQO1 targeting ability, improved cellular uptake, and/or different action mechanism. Significantly, complex 3 containing a coumarin moiety could be effectively activated in NQO1-overexpressed cancer cells to "turn on" fluorescence, showing a promising visual effect in cancer cells. In vivo study revealed that both 2 and 3 exhibited higher antitumor efficacy than cisplatin in the A549 xenograft mouse model at an equimolar dose to cisplatin. In all, the hybrids may serve as promising NQO1-targeting anticancer agents.