Bacterial biofilms are associated with a large number of infections. Biofilm-dwelling bacteria are particularly resistant to antibiotics, making it hard to eradicate biofilm-associated infections. Here, we use a novel cross-disciplinary approach combining microbiology and chemoinformatics to identify new and efficient anti-biofilm drugs. We found that ellagic acid (present in green tea) significantly inhibited biofilm formation of Streptococcus dysgalactiae. Based on ellagic acid, we performed in silico screening of the Chinese Natural Product Database to predict a 2nd-generation list of compounds with similar characteristics. One of these, esculetin, proved to be more efficient in preventing biofilm formation by Staphylococcus aureus. From esculetin a 3rd-generation list of compounds was predicted. One of them, fisetin, was even better to abolish biofilm formation than the two parent compounds. Fisetin dramatically inhibited biofilm formation of both S. aureus and S. dysgalactiae. The compounds did not affect planktonic growth in concentrations where they affected biofilm formation and appeared to be specific antagonists of biofilms. Arguably, since all three compounds are natural ingredients of dietary plants, they should be well-tolerated by humans. Our results indicate that such small plant components, with bacterial lifestyle altering properties are promising candidates for novel generations of antimicrobial drugs. The study underlines the potential in combining chemoinformatics and biofilm research.