The synthesis of some complex polyoxometalates (POMs) is critical to develop potential photocatalysts with high catalytic activity and selectivity. Here, we address this challenge by a hydrothermal self-assembly route to obtain a novel POM-based Co4W6O21(OH)2·4H2O with a hierarchical microsphere structure. The Co4W6O21(OH)2·4H2O crystallizes in the cubic space group Im3̅ with cell parameters: a = b = c = 12.878 Å, α = β = γ = 90°, and Z = 4. The structure is further characterized by X-ray diffraction, X-ray photoelectron spectroscopy, UV-vis spectroscopy, thermogravimetric analysis, and Fourier transform infrared spectra. After depositing Ag2O nanoparticles on the 3D Co4W6O21(OH)2·4H2O microsphere by photochemical synthesis, the Co4W6O21(OH)2·4H2O/Ag2O heterojunction presents enhanced photocatalytic activity for RhB compared with P25 and pristine Ag2O. Moreover, we confirm the key role of holes for the Co4W6O21(OH)2·4H2O/Ag2O and put forward a possible mechanism for the photocatalytic degradation reaction.