Legionella pneumophila, an environmental bacterium and intracellular pathogen of protozoa, is also a significant human pathogen, causing Legionnaires' disease and resulting in long-term lung damage. This bacterium possesses numerous virulence factors, of which ProA, an important extracellular zinc metalloprotease, plays a central role. ProA exhibits a broad substrate spectrum, including collagen fibers and immunogenic flagellin. This study focused on inhibiting ProA as a strategy to counteract L. pneumophila pathogenicity. The employed zinc-binding inhibitors effectively suppressed ProA cleavage of bacterial flagellin FlaA, which activates the TLR5 receptors of the host cell and consequently stimulates the pro-inflammatory NF-κB signaling pathway. Successful inhibition of this ProA-mediated immune evasion by FlaA degradation was confirmed in vitro using HEK-Blue™ hTLR5 cells. Moreover, the tested inhibitors demonstrated the ability to reduce the proteolytic degradation of native human collagen IV, a constituent of the basal lamina in human lungs. This suggests potential therapeutic approaches for reducing tissue damage associated with Legionellosis. In summary, this research provides insights into potential inhibitors to mitigate the effects of L. pneumophila infection and the importance of targeting ProA-mediated pathogenic mechanisms, particularly immune evasion and tissue damage.