Photothermal therapy (PTT) is considered an alternative for oncotherapy because it has less invasive damage to normal tissues than other methods, particularly in second near-infrared (NIR-II) PTT (1000–1350 nm) because of deeper biological tissue penetration, lower photon scattering, and higher maximum permissible exposure (1.0 W cm–2). However, for achieving a higher therapeutic effect, the delivery of large amounts of NIR-sensitive agents has been pursued, which in turn enormously increases damage to normal cells. Herein, we developed peptide-coated platinum nanoparticles (TPP-Pt) to create violent damage for a given amount of hyperthermia by purposefully delivering TPP-Pt to the thermally susceptible mitochondria with minimal side effects. Mitochondrial peptide targeting endowed ultrasmall platinum nanoparticles (PtNPs) with monodispersity, high stability, biosafety, and enhanced uptake of cancer cells and priority of mitochondria, causing efficient PTT. Moreover, an in vivo experiment showed that the excellent tumor inhibitory effect and negligible side effects could be achieved with the preferentially striking thermosensitive mitochondria strategy. The mitochondria-based “win by one move” therapeutic platform of peptide-coated platinum nanoparticles (TPP-Pt) demonstrated here will find great potential to overcome the challenges of low therapeutic efficiency and strong systemic side effects in PTT.