Aurones are a small subgroup of flavonoids in which the basic C₆–C₃–C₆ skeleton is arranged as (Z)-2-benzylidenebenzofuran-3(2H)-one. These compounds are structural isomers of flavones and flavonols, natural products reported as potent inhibitors of SARS-CoV-2 replication. Herein, we report the design, synthesis, and anti-SARS-CoV-2 activity of a series of 25 aurones bearing different oxygenated groups (OH, OCH₃, OCH₂OCH₃, OCH₂O, OCF₂H, and OCH₂C₆H₄R) at the A- and/or B-rings using cell-based screening assays. We observed that 12 of the 25 compounds exhibit EC₅₀ < 3 μM (8e, 8h, 8j, 8k, 8l, 8m, 8p, 8q, 8r, 8w, 8x, and 8y), of which five presented EC₅₀ < 1 μM (8h, 8m, 8p, 8q, and 8w) without evident cytotoxic effect in Calu-3 cells. The substitution of the A- and/or B-ring with OCH₃, OCH₂OCH₃, and OCF₂H groups seems beneficial for the antiviral activity, while the corresponding phenolic derivatives showed a significant decrease in the anti-SARS-CoV-2 activity. The most potent compound of the series, aurone 8q (EC₅₀ = 0.4 μM, SI = 2441.3), is 2 to 3 times more effective than the polyphenolic flavonoids myricetin (2) and baicalein (1), respectively. Investigation of the five more active compounds as inhibitors of SARS-CoV-2 3CL^pro based on molecular dynamic calculations suggested that these aurones should detach from the active site of 3CL^pro, and, probably, they could bind to another SARS-CoV-2 protein target (either receptor or enzyme).