Abstract 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 (MoO 3‐x ) nanoparticles. The morphologies of as‐prepared MoO 3‐x nanomaterials arranged from amorphous to crystalline with the reaction temperature varied from 160 °C, 180 °C to 200 °C, namely MoO 3‐x quantum dots (QDs), MoO 3‐x nanosheets, and MoO 2 nanospheres. Simultaneously, in the near‐infrared region (NIR), MoO 3‐x nanomaterials exhibit gradually enhanced localized surface plasmon resonance (LSPR) absorption, of which MoO 2 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 MoO 2 nanospheres have been systematically assessed in vitro and in vivo , respectively. The results revealed that MoO 2 nanospheres exhibit low toxicity and high therapeutic efficiency, making it an promising and effective photothermal agent in photothermal therapy