The thermally activated dynamics of methyl groups are important for biochemical activity as they allow for a more efficient sampling of the energy landscape. Here, we compare methyl rotations in the dry and variously hydrated states of three primary drugs under consideration to treat the recent coronavirus disease (COVID-19), namely, hydroxychloroquine and its sulfate, dexamethasone and its sodium diphosphate, and remdesivir. We find that the main driving force behind the considerable reduction in the activation energy for methyl rotations in the hydrated state is the hydration-induced disorder in the methyl group local environments. Furthermore, the activation energy for methyl rotations in the hydration-induced disordered state is much lower than that in an isolated drug molecule, indicating that neither isolated molecules nor periodic crystalline structures can be used to analyze the potential landscape governing the side group dynamics in drug molecules. Instead, only the explicitly considered disordered structures can provide insight.