In situ amorphization is an approach that enables a phase transition of a crystalline drug to its amorphous form immediately prior to administration. In this study, three different polyvinylpyrrolidones (PVP K12, K17 and K25) were selected to investigate the influence of the molecular weight of the polymer on the degree of amorphization of the model drug indomethacin (IND) upon microwaving. Powder mixtures of crystalline IND and the respective PVP were compacted at 1:2 (w/w) IND:PVP ratios, stored at 54% RH and subsequently microwaved with a total energy input of 90 or 180 kJ. After storage, all compacts had a similar moisture content (˜10% (w/w)). Upon microwaving with an energy input of 180 kJ, 58 ± 4% of IND in IND:PVP K12 compacts was amorphized, whereas 31 ± 8% of IND was amorphized by an energy input of 90 kJ. The drug stayed fully crystalline in all IND:PVP K17 and IND:PVP K25 compacts. After plasticization by moisture, PVP K12 reached a Tg below ambient temperature (16 ± 2 °C) indicating that the Tg of the plasticized polymer is a key factor for the success of in situ amorphization. DSC analysis showed that the amorphized drug was part of a ternary glass solution consisting of IND, PVP K12 and water. In dissolution tests, IND:PVP K12 compacts showed a delayed initial drug release due to a lack of compact disintegration, but reached a higher total drug release eventually. In summary, this study showed that the microwave assisted in situ amorphization was highly dependent on the Tg of the plasticized polymer.