Human dihydroorotate dehydrogenase (hDHODH), catalyzing the rate-limiting step of the pyrimidine biosynthesis pathway (PBP), is a drug target extensively investigated for various diseases including cancer, autoimmune disorders, and viral infections. We present evidence that the heterodimeric phloroglucinylpyrone arzanol potently inhibits hDHODH by competing with ubiquinone for binding to the lipophilic patch (LP) of the enzyme. Co-crystallization experiments on the enzyme-arzanol complex provided further insights into the binding pocket of hDHODH, revealing detailed features that could inspire the design of innovative inhibitors. The cellular translation of these enzymatic and biochemical data was validated in antiviral assays on SARS-CoV-2 infected cells. Taken together, these results exemplify the potential of natural products to explore novel areas of the protein druggable space and provide information relevant to multiple critical areas of drug discovery.