Colorectal cancer (CRC) is one of the most morbidity cancers, effective diagnosing and therapy is of great significance to prolong the patient survival. However, the diagnosis of CRC is usually in the advanced stage and it is difficult to completely resect tumor lesion during treatment. Herein, we develop a cascade-activatable NIR-II fluorescent inhibitor (Cu@IR783-CAI) for imaging-guided cuproptosis/chemodynamic combination therapy of CRC. Cu@IR783-CAI is synthesized by sequentially modifying copper complex and benzenesulfonamide moiety onto a NIR-II fluorescence dye IR783. The NIR-II fluorescence signal is quenched by copper complex via donor-excited photoinduced electron transfer (d-PeT) process under physiological condition. Under CRC microenvironment, the overexpressed hydrogen sulfide (H2S) can react with copper complex to generate copper sulfide, which hinders the d-PeT process and recovers the NIR-II fluorescence signal. Furthermore, Cu@IR783-CAI is able to target carbonic anhydrase IX (CA IX) overexpressed on the surface of tumor cells, leading to the restriction of intramolecular rotation and further enhancement of NIR-II fluorescence signal, achieving the cascade activation. On the other hand, copper complex of Cu@IR783-CAI can simultaneously trigger cuproptosis and chemodynamic therapy within tumor cells, which shows satisfactory anticancer efficacy both in vitro and in vivo. Thus, our study provides a smart NIR-II fluorescent CA inhibitor with cascade-activatable feature for CRC theranostics.