In this study, we demonstrate an easy particle-mediated protocol using the specific structure of mesocrystal Ag2O sacrificial templates to synthesize highly rough-cubic Ag mesocages. To the best of our knowledge, the mesocrystal particles are reported for the first time as sacrificial templates for synthesizing metal particles. The obtained Ag mesocages show high surface-enhanced Raman scattering (SERS) sensitivity because of the highly rough topography formed by arrays of uniform individual Ag nanoparticles. Abundant “hot spots” with greatly enhanced local electromagnetic field are promoted densely on the mesocage surface by the plenty of deep and narrow gaps and the hollow structure. The single-particle SERS signal generated by the Ag mesocage has an enhancement factor of approximately 109, which is approximately four times higher than the Ag mesocage synthesized using single-crystal Ag2O particle as a template. Meanwhile, this signal displays a linear dependence on the detected analyte concentration, sensitively down to 1.0 × 10−12 m.