Heparanase (HPSE) is a mammalian endo-β-D-glucuronidase. It cleaves heparan sulphate (HS) side chains of heparin sulphate proteoglycans (HSPG), which are composed of repeating polysulfated disaccharide units of glucosamine and hexuronic acid residues. By degrading HS into smaller fractions, heparanase controls the availability of chemokines, growth factors and a plethora of other bioactive molecules, thus enabling the release of saccharide fragments that end up activating multitude of signaling processes. When overexpressed, HPSE has been correlated with tumor growth and survival as well as chronic inflammation exhibited in several diseases, the latest of them being the COVID-19 pandemic caused by SARS-CoV-2. Thus, it has become increasingly important in clinic to search for compounds that may potentially inhibit HPSE. In this study, we combined virtual screening and molecular docking of publicly known chemical databases in order to identify small molecules that can be developed into novel HPSE inhibitors. We were able to identify promising new chemotypes through the structural rationalization of the interactions previously reported compounds. These novel potential HPSE inhibitors are shown to exhibit optimized in silico druggability and docking properties and can potentially serve as pharmacological tools to treat chronic and infectious diseases associated with chronic inflammation.