The solubility of drugs in polymer matrixes has been recognized as one of the key factors governing the physical stability of solid dispersions. This study has explored the implications of drug solubility on the destabilization that occurs on milling, which is often used as an additional process for hot melt extruded (HME) solid dispersions. The theoretical drug solubility in the polymer was first predicted using various theoretical and experimental approaches. The destabilization effects of high-energy mechanical milling on the solid dispersions with drug loadings below and above the predicted solubility were then investigated using a range of thermal, microscopic, and spectroscopic techniques. Four model drug-polymer combinations were studied. The HME formulations with drug loading below the predicted solid solubility (undersaturated and true molecular dispersion) showed good stability against milling. In contrast, milling destabilized supersaturated HME dispersions via increasing molecular mobility and creating phase-separated, amorphous, drug-rich domains. However, these additional amorphous drug-rich domains created by milling show good stability under ambient conditions, though crystallization can be accelerated by additional heating. These results highlighted that the processing method used to prepare the solid dispersions may play a role in facilitating the stabilization of amorphous drug in supersaturated solid dispersions. The degree of supersaturation of the drug in the polymer showed significant impact on the destabilization behavior of milling on solid dispersions. An improved understanding of the destabilization behavior of solid dispersions upon milling can provide new insights into the processing related apparent solubility of drugs in polymers.