Herein, HMSSs were successfully synthesized using the sonochemical method. Compared with a conventional synthesis under continuous stirring, HMSSs synthesized under ultrasound irradiation were uniform hollow spheres with a thinner mesoporous shell, resulting in higher pore volumes and larger specific surface areas. The hollow cores were acquired without the templates but from ethanol droplets generated in situ by ultrasound. The ethanol/water volume ratio (E/W) affected the structures of sonochemical synthesized particles, i.e., mesoporous silica particles were obtained at low E/W before transforming to HMSSs under moderate E/W and dense silica spheres at high E/W. Varying [NH4OH] base catalysts in an aqueous phase altered the core structure of HMSSs from hollow cores at high [NH4OH] to partial-filled cores at a moderate concentration and non-hollow cores at low [NH4OH]. Ultrasound was effectively utilized to prepare curcumin-loaded HMSSs in a single step. Stable ethanol droplets containing curcumin were produced from the ultrasound's homogenizing effect, leading to curcumin's encapsulation within HMSSs. While the cavitation induced the chemical effect, reducing the reaction time. The encapsulation of curcumin and the formation of HMSSs could occur concurrently; thus, not only is the drug loading step unnecessary, but the efficiency of loading drugs inside HMSSs is also enhanced.