Two polymorphs of famotidine were prepared by recrystallization from acetonitrile for form A and methanol for form B, respectively. The effect of grinding process on the polymorphic transformation of famotidine was investigated. Each famotidine sample ground for various grinding times in a ceramic mortar was determined by differential scanning calorimetry (DSC), conventional and thermal Fourier transform infrared (FT-IR) microspectroscopy. The results indicate that the raw material of famotidine was proved to be a form B. A unique IR absorption band at 3505 cm−1 for famotidine form B gradually decreased its intensity with the grinding time, while two newer IR absorption bands at 3451 and 1671 cm−1 for famotidine form A slowly appeared. The peak intensity ratio of 3451/3505 cm−1 was linearly (r = 0.9901) increased with the grinding time, suggesting that the grinding process could induce the polymorphic transformation of famotidine from form B to form A by a zero-order process. The DSC endothermic peaks also confirmed this polymorphic transformation from famotidine form B (167 °C, ΔH: 165 J/g) to famotidine form A (174 °C, ΔH: 148 J/g) in which the values of enthalpy were linearly reduced with the increase of grinding time (r = 0.9943). The phase transition temperature of the different ground famotidine samples could be easily and only evidenced by using thermal FT-IR microspectroscopy, rather than by DSC analysis. These phase transition temperatures of the famotidine form B ground for 5–20 min quickly reduced from 144 to 134 °C and maintained a constant at 134 °C even after 20–30 min grinding. The grinding process not only decreased the crystallinity of famotidine form B but also reduced the particle size of famotidine form B, resulting in easy induction of the polymorphic transformation of famotidine from form B to form A in ground famotidine sample.