Numerous efforts have been devoted to improving the solubility of poorly water-soluble drugs. Recently, it was reported that the use of metal-organic frameworks (MOFs), which are a new class of porous materials consisting of metal ions and organic ligands, is effective in improving the solubility of poorly water-soluble drugs. Our previous study demonstrated an improvement in the solubility of indomethacin (IDM) triggered by the zeolitic imidazolate framework-8 (ZIF-8). The present study aimed to elucidate the solubilization mechanism using the ZIF series, namely, ZIF-8, ZIF-67, and ZIF-L. It was confirmed that the solubility of ZIF-trapped IDM and ibuprofen (IBU) was enhanced compared to the raw drugs, regardless of the ZIF type. This study focused on 2-methylimidazole (2-MIM), which is commonly used as a ZIF organic ligand. Both IDM and IBU were easily dissolved by the addition of 2-MIM, suggesting that the presence of 2-MIM enhanced the solubility of the drugs. Inductively coupled plasma measurements also confirmed the presence of metal ions of ZIFs in the supernatant solution after the drug release tests, indicating the decomposition of ZIFs during drug release. The findings of this study demonstrated the solubilization mechanism of poorly water-soluble drugs using ZIF particles. We observed that the drugs loaded on the ZIFs were released simultaneously with the decomposition of some of the ZIFs. The 2-MIM molecules were also released concurrently. The presence of 2-MIM improved the solubility of poorly water-soluble drugs.