High-valent oxo-rhenium(v) (oxo-Re(v)) complexes are emerging as potential alternatives to platinum (Pt)-based chemotherapeutics. While potent in vitro antitumor activity, novel mechanism of action, and low Pt-cross resistance of oxo-Re(v) complexes are highly encouraging, their further development and clinical potential are mainly limited by their poor hydrolytic stability. To overcome this limitation, we performed a systematic investigation which led to the identification of the first hydrolytically stable oxo-Re(v) complex, namely, [(TPB)Re( O)(O-CH2-CH2-O)] (TPB = tri(1-pyrazolyl)borohydride), with potent in vitro antitumor activity against a panel of Pt-sensitive and Pt-resistant cancer cell lines. Detailed mechanistic investigations confirmed that in addition to nuclear accumulation and profound DNA damage, the oxo-Re(v) complex localized in the mitochondria and caused mitochondrial dysfunction, induced ROS, and elevated endoplasmic reticulum stress. This multi-pronged novel mechanism of action triggered dual apoptosis- and necroptosis-mediated cell death. Importantly, the oxo-Re(v) complex presented strong synergistic antitumor activity in combination with cisplatin. Encouragingly, our in vivo biocompatibility study using zebrafish confirmed that the oxo-Re(v) complex is non-toxic to animals at its therapeutically relevant doses. In particular, here we report a hydrolytically stable oxo-Re(v) antitumor complex with potent antitumor activity when applied as a single agent or in combination with cisplatin, with negligible toxicity, paving the way for the development of clinically competent oxo-Re(v)-based antitumor agents.