Semiconductor nanocrystals showing surface plasmonic absorption features can be used as prospective substitutes for noble metallic nanoparticles. Herein, a creative one‐pot hydrothermal route without template is used to synthesize plasmonic oxygen deficiency molybdenum oxide (MoO3‐x) nanoparticles. The morphologies of as‐prepared MoO3‐x nanomaterials arranged from amorphous to crystalline with the reaction temperature varied from 160 °C, 180 °C to 200 °C, namely MoO3‐x quantum dots (QDs), MoO3‐x nanosheets, and MoO2 nanospheres. Simultaneously, in the near‐infrared region (NIR), MoO3‐x nanomaterials exhibit gradually enhanced localized surface plasmon resonance (LSPR) absorption, of which MoO2 nanospheres exhibit intense NIR absorption with a photothermal conversion efficiency up to 72.5% under 808 nm NIR laser irradiation. Moreover, the toxicity and cancer therapy efficacy of MoO2 nanospheres have been systematically assessed in vitro and in vivo, respectively. The results revealed that MoO2 nanospheres exhibit low toxicity and high therapeutic efficiency, making it an promising and effective photothermal agent in photothermal therapy