<p>Carbohydrate chemistry continues to provide versatile routes toward new bioactive compounds, yet limited solubility often restricts their broader applications. In the present study, <i>N</i>-fluoroamide thioglycoside derivatives were synthesized in a short and mild process starting from 1,3,4,6-tetra-<i>O</i>-acetyl-2-amino-2-deoxy-<i>β</i>-<i>D</i>-glucopyranose hydrochloride. The transformation employed a fluorous acylating agent in the presence of potassium carbonate and thiophenol, affording the desired products in excellent yields (82–95%) within 20 min. Since these compounds showed poor solubility in water, host–guest complexes were generated with native Betadex (<i>β</i>-Cyclodextrin) under ultrasound assistance. The resulting inclusion complexes were confirmed by ¹H, ¹³C, ¹⁹F NMR, FT–IR spectroscopy, and X-ray diffraction. UV–visible measurements demonstrated a marked enhancement in aqueous solubility, reaching up to a fourteen-fold increase, consistent with a 1:1 AL-type stoichiometry obtained from phase-solubility analysis. Biological assays revealed that encapsulation in <i>β</i>-CD not only improved dissolution but also strengthened antimicrobial activity. This approach highlights a practical strategy that combines rapid synthesis, supramolecular encapsulation, and enhanced bioactivity, opening new perspectives for the pharmaceutical development of fluorinated sugar derivatives.</p> Graphical abstract <p>A rapid ultrasound-assisted approach was successfully developed for the synthesis of <i>N</i>-fluoroamide thioglycosides under mild reaction conditions. Furthermore, complexation with <i>β</i>-cyclodextrin markedly improved the aqueous solubility of the synthesized compounds and enhanced their antimicrobial activity through the formation of stable host–guest supramolecular inclusion complexes.</p>