Herein, we report a detailed study of microwave-matter interaction focused on the role of small nanoparticles and the effects on microwave thermal heating. We have used a model reaction (degradation of methylene blue) to study the influence of temperature, size, and catalytic properties of the nanoparticles in the potential formation of hot spots. Total mineralization was achieved after 3 h microwave heating at 200 °C in the presence of 2 nm TiO2 nanoparticles (92% calculated TOC decay), but the reaction resulted in a mixture of intermediates (52% TOC decay) in the absence of TiO2. The effect of temperature was evaluated by carrying out the reaction at 120 °C, and the results were similar to those obtained in the absence of TiO2, but with lower TOC removal efficiencies (12-14%). For comparison, the degradation of MB was also followed using (noncatalytic) SiO2 and MnO2 nanoparticles of comparable size. Differences in the degradation efficiency may be ascribed to the formation of hot spots at the particles surface, as a result of large heat accumulation liable to provide enough energy to the system to accomplish C-C bond break and to achieve total mineralization.