Anchoring metal cores inside porous shells can endow metal catalyst with high selectivity and stability. Herein, multiple silver nanoparticles were successfully anchored in hollow mesoporous silica nanospheres (Ag@HMSNs) through a facile one-pot method. Polyacrylic acid aggregates self-assembled in water/ethanol solvent were used as core templates and Ag nanoparticles captors, and hexadecyl trimethoxysilane (C₁₆TMS) was used as the pore-making agent. The hollow cavity, encapsulated multiple Ag nanoparticles, and mesoporous silica shell of the Ag@HMSNs were confirmed by X-ray powder diffraction (XRD), transmission electron microscopy (TEM), and nitrogen sorption analysis. Just as expected, Ag nanoparticles (2–5 nm) were encapsulated in the cavity of hollow mesoporous silica nanospheres with the size of about 200 nm. The fabricated Ag@HMSNs showed excellent performance for catalytic reduction of p-nitrophenol (4-NP). Also, catalytic activity of the Ag@HMSNs for 4-NP reduction was increased with the addition amount of the pore-making agents and surface areas. The superior catalytic performance was attributed to the unique structural features of Ag@HMSNs architecture, in which the mesoporous shell provided readily accessible pathway for fast transport of reactants to the encapsulated Ag nanoparticles.