Phototheranostics that integrate diagnosis and treatment modalities have shown great promise in personalized cancer therapy. However, the “always on” characteristics often lead to suboptimal imaging quality and severe side effects. Herein, we report the construction of a perylenemonoimide based nanodrug CPMI NP with multi-functional activatable theranostic capability. The nanodrug is facilely co-assembled from a prodrug CPMI and DSPE-mPEG2000. In a tumor microenvironment (TME) with excessive glutathione (GSH), CPMI undergoes a cascade reaction to generate the phototheranostic molecule NPMI and the chemodrug chlorambucil, simultaneously switching on the near-infrared (NIR) fluorescence, photothermal effect, and drug release. The photothermal conversion efficiency is as high as 52.2%. Moreover, NPMI exhibits an enhanced intermolecular π–π stacking effect, leading to significant size-enlargement of the nanodrug and prolonged tumor retention. Due to TME-activation, the strong in vivo fluorescence signal of the tumor can be observed 144 h post injection with a high signal-to-noise ratio of up to 17. The enhanced tumor inhibition efficiency of the nanodrug is confirmed through activatable chemo-photothermal therapy. This work paves the way for the design of activatable phototheranostic agents for accurate cancer diagnosis and treatment.