The papain-like protease (PLPro) is a highly conserved, non-structural protein that plays a crucial role in the formation of the replication-transcription complex and the processing of polyproteins in SARS-CoV-2, as well as improving the host’s antiviral immune responses against said virus. Chalcone is a common ingredient, which can be found in a multitude of natural substances, such as food and herbs. It has been proven to have various biological activities, including antiviral effects. Previous studies have identified several natural chalcone-based compounds with the ability to inhibit SARS-CoV-2 by targeting the PLPro enzyme. Based on these findings, this study investigated potential chalcone-derived PLPro inhibitors, as retrieved from Pubchem and in-house libraries. Virtual screening protocols, specifically molecular docking and molecular dynamics simulating filter, were applied to reach the desired goal. As a result, 1448 out of 1454 chalcone derivatives can effectively bind to SARS-CoV-2 via PLPro. The 5 substances with the most suitable docking score and binding mode were selected for the next step. Through MD, CID1021201513 and CID101585417 showed the greatest potential in targeting PLPro. However, further in vitro and in vivo studies must be conducted before the bio-activities of these chalcones against SARS-CoV-2 can be confirmed. Furthermore, the ligand-protein interaction mode analysed in this research can help design effective chalcone derivatives.