Photoacoustic (PA) probes have been developed very quickly and applied in broad areas in recent years. Most of them are constructed based on organic dyes with intrinsic near-infrared (NIR) absorption properties. To increase PA contrast and improve imaging resolution and the sensitivity of detection, various methods for the design of PA probes have been developed. This minireview mainly focuses on the development and design strategies of activatable small-molecule PA probes in four aspects: reaction-cleavage, metal ion chelation, photoswitch, and protonation-deprotonation. It highlights some key points of designing PA probes corresponding to their properties and applications. The challenges and perspectives for small-molecule PA probes are also discussed.