The effect of environmental humidity and additional water added on the polymorphic change of famotidine in the process of grinding was investigated. The famotidine form B powder with or without additional amount of water added was respectively ground for 30 min in an oscillatory ball mill under 25 ± 2 °C and three relative humidities (RH) (50 ± 5%, 75 ± 5% or 95 ± 5% RH). Each ground sample was periodically isolated for analytical determinations by using differential scanning calorimetry (DSC), thermogravimetric (TG) analysis and Fourier transform infrared (FT-IR) microspectroscopy. The results indicate that the higher environmental humidity might induce and promote the polymorphic transformation of famotidine from form B to form A in the process of grinding. Moreover, the more the amount of water externally added the easier the polymorphic transformation of famotidine from form B to form A obtained. In addition, the more grinding time spent the more formation of form A obtained. This study disavowed the results of other studies in which no polymorphic change of famotidine even by grinding. The apparent evidence shows that the solid-state polymorphic transformation of famotidine from form B to form A in the grinding process significantly depended on the relative humidity of atmosphere and the additional amount of water added.