The pest of monolithic poly- and single-crystalline molybdenum disilicide, as well as its composites, has been investigated by low temperature oxidation in air at temperatures ranging from 350 to 700 °C. Pest phenomenon (i.e., disintegration from bulk into powders) was consistently observed from samples oxidized at temperatures between 375 and 500 °C. In contrast, samples oxidized at 550 °C exhibited only severe cracking, and samples oxidized at 350 °C or at/above 600 °C were intact. The pested samples resulted in powdery products consisting of MoO3 whiskers, SiO2 clusters, and residual MoSi2. The MoO3 whiskers exhibited protruding characteristics, and were highly concentrated at microstructural heterogeneous sites, such as interparticle boundaries, grain boundaries, and cracks. Blisters were observed and found to be formed predominantly on the grain boundary and interparticle boundary interfaces of tested samples. These blisters were often found to be erupted, indicating that significant vapor pressure was built up underneath the sample surface. Interrupted oxidation tests at 500 °C revealed that a substantial volume change also occurred. The development of the pest of MoSi2 was found, macroscopically, to consist of nucleation and growth. In most cases, it initiated from some local microstructural inhomogeneities, and propagated throughout the samples. Based on the morphologies of disintegrated powders, two different kinetic processes were identified to be responsible for the pest reaction. According to the results from single crystals, the pest of MoSi2 appeared to be kinetically controlled by the formation and volatilization of MoO3. The mechanism of MoSi2 pest is proposed and discussed. Thermodynamic analyses are also presented to substantiate the experimental observations.