Abstract Second near‐infrared (NIR‐II) light is desired to drive photocatalytic therapy owing to its high tissue penetrability and operationality, but the efficiency of direct NIR‐II‐photocatalytic H 2 generation is negligible owing to a trade‐off between narrow semiconductor bandgap and high redox potential. Here, this work proposes a new concept of photothermal‐pyroelectric cascade catalysis (photopyroelectric catalysis) to circumvent the trade‐off for enhanced NIR‐II light‐driven catalytic efficiency, and develop a novel kind of multifunctional ZnS:Cu nanoparticles with a wide bandgap (2.7 eV) and high NIR‐II‐photothermal (52.4%) and pyroelectric efficiencies (0.44 mC m −2 K −1 ), realizing high efficacy of NIR‐II light‐driven catalytical H 2 generation (8.7 mmol g −1 h −1 ). Under NIR‐II laser irradiation, intratumoral ZnS:Cu nanoparticles locally utilize thermal energy during both photothermal heating and natural cooling for pyroelectrocatalytic H 2 generation and oxidative depletion of intratumorally overexpressed glutathione, which induce tumor immunoactivation and ferroptosis, respectively, achieving high‐efficacy synergetic therapy of tumor. This work opens an avenue for exploiting NIR‐II light for efficient catalysis in the fields of both solar energy and catalytic medicine.