Background: Proprotein Convertases (PCs) or Proprotein Convertase Subtilisin/Kexins (PCSKs) belong to a family of calcium-dependent endoproteases that are structurally related to bacterial subtilisin and yeast kexin. These enzymes play major roles in the processing of inactive precursor proteins producing their bioactive mature forms that are implicated in a wide variety of diseases including cancer, viral and bacterial infections. As a result, PCs are major targets for intervention of these diseases. Objective: Our objective in this study is to find non-peptide inhibitors of PC-enzymes from a potential natural source. Results: Herein we describe several natural flavonoid compounds as inhibitors of PC-enzymes including furin, a key member. These compounds were isolated from the medicinal plant Oroxylum indicum, fully characterized and tested in vitro for their PC-inhibitory property against the fluorogenic peptide substrate, Boc-RVRR-MCA (Boc = tert-butyloxy carbonyl, MCA = 4-Methyl coumarin7-amide). The measured Ki and IC50 were found to be in low μM ranges. A comparative analysis of inhibition against furin, PC4, PC5 and PC7 suggested a partial selectivity towards PC4. These flavonoids also blocked efficiently the PC4-mediated processing of a fluorogenic peptide derived from the processing site of its substrate, pro-Insulin Growth Factor-1 (proIGF-1). This anti-protease activity may provide a rationale for the observed anticancer and anti-HIV properties of some of these flavonoid compounds. This is the first demonstration of anti-PC activity of flavonoid compounds.