With the expansion of gel research, organic small molecule gels are beginning to gain attention. Whether the small-molecule gel approach can be a new formulation strategy of solubilization and permeation promotion for poorly soluble drugs needs to be explored in this study. The model ingredient indomethacin (IND) as a nonsteroidal anti-flammatory drug shows limited therapeutic application mainly due to its low water solubility. Herein, the IND small molecule hydrogel was design to co-formed with a small molecule ligand by integrating theory-model-experiment techniques. Then, the formed IND small molecule hydrogels (i.e., IND-MEG hydrogel and IND-ARG hydrogel) with meglumine (MEG) or arginine (ARG) appeared typical 3-D network with good rheology. In comparison to crystalline IND, the solubilities of IND-MEG hydrogel and IND-ARG hydrogel exhibited 506.71-fold and 479.63-fold improvements, respectively. Meanwhile, both IND hydrogels performed significantly enhanced release rate and degree, and maintained supersaturation for a long time arising from the complexation reaction of IND and ligand, which was revealed by phase solubility and fluorescence quenching studies. Furthermore, the designed IND hydrogels significantly promoted IND membrane permeability compared to the commercial IND hydrogel, and enhanced the development potential of novel IND hydrogels for oral and transdermal applications. Therefore, this study provides a new formulation technique to increase the solubility/release and permeability of poorly water-soluble drugs by designing their small molecule hydrogel systems.