Techniques for the qualitative and quantitative detection of H2S in vivo have attracted considerable attention due to the key role of H2S in various physiological and pathological processes. However, in vivo detection strategies for H2S are mainly based on fluorescence imaging, which is limited by its poor tissue penetration. Moreover, the limitations of single-mode probes are amplified in complex physiological environments. Herein, a core-shell Fe3O4@Cu2O nanoparticle was constructed as a magnetic-photoacoustic dual-mode probe for H2S detection in vitro and in vivo based on the in situ response of Cu2O to endogenous H2S in colon tumors. This probe is expected to greatly improve the accuracy of H2S detection in vivo because it employs two detection methods with complementary advantages. The new probe was experimentally applied to the in vivo and in vitro visualization of H2S in mice with colorectal cancer, validating the in situ reaction-activated dual-detection method. This work establishes a simple and efficient dual-mode imaging method based on a novel trigger mechanism. The findings provide a new strategy for colon cancer detection based on the in situ reactions at tumor sites.