It has been more than four years since the first report of SARS-CoV-2, the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, the scientific community is focused on vaccine development in an exceptionally rapid time frame, as well as the evaluation of a wide range of potential treatments in clinical trials, a few of which have also reached the market. However, these drugs are characterized by several limits (including low response to treatment in some patients, low effectiveness against the new variants, severe side effects, etc.), thus underscoring the need to speed up the research. Among potential antiviral targets, the SARS-CoV-2 nonstructural protein 13 (nsp13) is highly promising thanks to its pivotal role in viral replication. Pursuing the studies on the development of nsp13 inhibitors, herein, the design, synthesis, and biological evaluation of new SARS-CoV-2 nsp13 inhibitors are reported. In general, the newly designed dikehexenoic derivatives are proven active against both the enzymatic activities showing measurable IC