AbstractAntiviral therapy based on neuraminidase (oseltamivir) or polymerase (baloxavir marboxil) inhibitors plays an important role in the management of influenza infections. However, the emergence of drug resistance and the uncontrolled inflammatory response are major limitations in the treatment of severe influenza disease. Protectins D1 (PD1) and DX (PDX), part of a family of pro‐resolving mediators, have previously demonstrated anti‐influenza activity as well as anti‐inflammatory properties in various clinical contexts. Herein, we synthetized a series of simplified PDX analogs and assessed their in vitro antiviral activity against influenza A(H1N1) viruses, including oseltamivir‐ and baloxavir‐resistant variants. In ST6GalI‐MDCK cells, the PDX analog AN‐137B reduced viral replication in a dose‐dependent manner with IC50 values of 23.8 for A/Puerto Rico/8/1934 (H1N1) and between 32.6 and 36.7 µM for susceptible and resistant A(H1N1)pdm09 viruses. In MTS‐based cell viability experiments, AN‐137B showed a 50% cellular cytotoxicity (CC50) of 638.7 µM with a resulting selectivity index of 26.8. Of greater importance, the combination of AN‐137B with oseltamivir or baloxavir resulted in synergistic and additive in vitro effects, respectively. Treatment of lipopolysaccharide (LPS)‐stimulated macrophages with AN‐137B resulted in a decrease of iNOS activity as shown by the reduction of nitrite production, suggesting an anti‐inflammatory effect. In conclusion, our results indicate that the protectin analog AN‐137B constitutes an interesting therapeutic modality against influenza A virus, warranting further evaluation in animal models.