Influenza virus (IV) infections usually cause acute lung injury characterized by exaggerated proinflammatory responses. The paucity of therapeutic strategies that target host immune response to attenuate lung injury poses a substantial challenge in management of IV infections. In this study, we chemically synthesized a novel fatty acid (2Z,4E)-deca-2,4-dienoic acid (DDEA) identified from Chinese Cordyceps by using UHPLC-Q-TOF-MS techniques. The DDEA did not inhibit H1N1 virus replication but attenuated proinflammatory responses by reducing mRNA and protein levels of TNF-α, IFN-α, IFN-β, IL-6, CXCL-8/IL-8, CCL-2/MCP-1, CXCL-10/IP-10, CCL-3/MIP-1α, and CCL-4/MIP-1β in A549 cells and U937-derived macrophages. The anti-inflammatory effect occurred through downregulations of TLR-3-, RIG-I-, and type I IFN-activated innate immune signaling pathways. Altogether, our results indicate that DDEA may potentially be used as an anti-inflammatory therapy for the treatment of IV infections. © 2021 The Authors. Published by American Chemical Society.