With two different methods, ibuprofen was entrapped into porous hollow silica nanoparticles (PHSNs) carriers, which were synthesized through a sol-gel route by using CaCO3 nanoparticles as the inorganic templates. By employing pressured CO2 as the loading medium, the amount of ibuprofen that was pressed into the carriers was approximately 52% higher than that by simply soaking. The drug release behaviors of the ibuprofen-loaded PHSNs were investigated in a simulated intestine juice and an artificial gastric fluid, respectively, and it demonstrated a sustained release pattern in all cases and the sample prepared under high pressure had a lower release rate in both fluids and thus owned a greater sustained drug release capacity. In the acidic artificial gastric fluid, no silica was degraded and only 16% of the loaded ibuprofen was released from the matrix in 300 min. However, much more silica was degraded in the simulated intestine juice in a shorter time and almost all the loaded ibuprofen was dissolved into the solution eventually, resulting in a quicker and complete ibuprofen release. Therefore, the PHSNs can be utilized for applications of controlled drug delivery to small intestine.