This study investigated the potential use of mesoporous silica nanoparticles (MSNs) as a carrier for duloxetine hydrochloride (DX), which is prone to acid degradation. Sol-gel and solvothermal methods were used to synthesize the MSNs, which, after calcination and drug loading, were then characterized using X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET) technique, thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and diffuse reflectance ultraviolet-visible (DRS-UV-Vis) spectroscopy. Releases of DX from the MSNs were good in pH 7.4 (90%) phosphate buffer but poor in acidic pH (40%). In a comparative release study between the MSNs in phosphate buffer, TW60-3DX showed sustained release for 140 h, which was higher than the other nanoparticles. The mechanism of DX release from the MSNs was studied using Peppas kinetics model. The "n" value of all three MSNs ranged from 0.45 to 1 with a correlation coefficient (r (2)) >0.9, which indicated that the release of the drug from the system follows the anomalous transport or non-Fickian diffusion. The results supported the efficacy of mesoporous silica nanoparticles synthesized here as a promising carrier for duloxetine hydrochloride with higher drug loading and greater pH-sensitive release.