Introduction: Drugs classified as class IV by the Biopharmaceutical Classification System present significant problems in relation to effective oral administration. In the case of antibiotics, the subsequently high doses required can enhance the emergence of microorganism resistance and lead to a low rate of patient treatment adherence. Objective: In an attempt to improve physicochemical properties and microbiological activity of norfloxacin, the aim of this study was to investigate different methods (coevaporation, kneading followed by freeze-drying or spray-drying) to obtain complexes of norfloxacin and different cyclodextrins. Methods: Guest–host interactions were investigated through a complete physical–chemical characterization and the dissolution profile and microbiological activity were determined. Results: The formation of a complex of norfloxacin and β-cyclodextrin (1:1), obtained by kneading followed by freeze drying, led to increased drug solubility, which could maximize the oral drug absorption. Conclusion: Moreover, the microbiological activity was enhanced by around 23.3%, demonstrating that the complex formed could represent an efficient drug delivery system.