Bile salt based low-molecular-weight supramolecular hydrogels (LMWSH) serve as an appealing framework for drug delivery applications, owing to their natural origin, biocompatibility, and the peculiar distribution of hydrophobic and hydrophilic domains. In this work, LMWSH based on an ionotropic gel of sodium cholate assisted by Ca2+ ions (CaC) was developed as a drug delivery system for both hydrophilic and hydrophobic drugs. Diosgenin, Quercetin, Rutin, and Amygdalin were chosen as model drugs, having varying hydrophobicity. The mechanical strength of the CaC hydrogel is enhanced by increasing the hydrophobicity of the loaded drug. The close-knit mesh design of CaC hydrogels loaded with hydrophobic drugs resulted in controlled drug release compared to the hydrophilic drugs. Drug-loaded CaC hydrogels exhibited good swelling and thixotropy, making them suitable for injectable formulations. In kinetic drug release, both relaxation and diffusion mechanisms play a pivotal role. The antioxidant and antibacterial activity of the loaded drugs increased synergistically in the hydrogels. Thus, due to these properties, the hydrogels can be safely used as topical gels against wound healing. This study shows that bile salts exhibit potential to enhance the delivery of both hydrophobic and hydrophilic drugs, making them promising candidates for biomedical applications.