AbstractEmerging stimuli‐responsive composite probes active in the second near‐infrared window (NIR‐II, 1000–1700 nm) hold vast potential for improving in vivo imaging performance with minimized noise interference. The interactions among external irradiation, shell species, and the emissive core are key factors in the design of smart structures. The external irradiation provides energy for shell species and the emissive core to generate intense NIR‐II fluorescence signals, while the energy transfer process hinders NIR‐II emission in the inner structure of smart composite probes. However, if pathophysiological stimuli interrupt the above processes, then NIR‐II fluorescence signals are recovered. This review covers NIR‐II imaging based on diverse smart composite NIR‐II fluorescent probes responding to various biological stimuli, including ONOO−, overexpressed reactive sulfur species, abnormally expressed enzymes, and abnormal levels of physiological metabolites. Finally, to appreciate these advances, the challenges and perspectives of stimuli‐responsive composite NIR‐II probes are highlighted.