In the process of discovery and development of APIs (Active Pharmaceutical Ingredients), the rate of solubility or aqueous dissolution plays a very important role from the first evaluations of the candidates to the development of final marketable products. Since only the solubilized form of an active ingredient is capable of being transported and exerting its therapeutic effect across biological membranes, it is of utmost importance to control its solubility. However, the number of APIs under development with low water solubility has notoriously grown in recent years. Their pharmaceutical use will face problems such as insufficient bioavailability, late onset of action, and the need for large dosages.The present study aims to evaluate the behavior of ciprofloxacin and norfloxacin (fluoroquinolones), as model APIs for their different solubilities, in aqueous and non-aqueous natural deep eutectic solvents (NADES). The main objective is to improve the solubility of both drugs in pharmaceutical studies and analytical applications. In order to do so, two sets of eutectic solvents were selected, each composed with a polar solvent, an intermediate one, and a nonpolar solvent, as well. Very promising results were obtained in NADES of polar and intermediate polarity, for both drugs. In addition, the physicochemical characterization of such solvents was carried out to better understand the aforementioned results.