The use of co-solvents to increase drug solubility is limited mainly due to their toxicity. Many solvents are not biodegradable and have significant environmental impact. Furthermore, uncontrolled precipitation of the compound may arise when solvent-based formulation is introduced into an aqueous medium. Cyclodextrins (CD) can form inclusion complexes resulting in an increase in the guest's solubility. Herein, we evaluated the effect of dimethylsulfoxide (DMSO), ethanol (EtOH), CD, and their association, on the solubility of two natural anti-oxidants, trans-anethole (AN) and caffeic acid (CA). The findings revealed that co-solvents or CD enhanced the solubility of these compounds. Nonetheless, if the concomitant presence of co-solvent and CD induced a loss of the solubilizing efficiency of CD it allowed lowering the quantity of solvent needed to achieve the same solubility. Consequently, the concentration of CD and co-solvent in the complexation media should be optimized to solubilize the required amount of the guest.