Fluorite has been used as an activating heterogeneous catalyst for a rapid and facile one-pot synthesis of biologically active Ugi four-component reaction (Ugi-4CR) under microwave irradiation in good to moderate yields with short reaction times. The catalyst is environmentally benign, commercially available, and reusable several times with no reduction in its efficiency. The resulting Ugi derivatives 5(a–h) were characterized on the basis of 1H and 13C NMR, infrared, elemental analysis, and mass spectral data. The synthesized moieties were screened for their potential antibacterial activities in vitro against a few microorganisms: Staphylococcus aureus (Gram positive), Bacillus subtilis (Gram positive), Escherichia coli (Gram negative), and Proteus vulgaris (Gram negative). The screening data show that compounds 5a, 5c, 5e, and 5h are highly active against the strains. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]