Host restriction factors and viral evasion strategies involved in the virus-host arms races remain to be discovered. Through an initial membrane protein-targeted CRISPR-Cas9 screening, we identified Acyl-CoA synthetase long-chain family member 3 (ACSL3) as a restriction factor against influenza A virus (IAV). Clinical transcriptomic analysis shows that ACSL3 is upregulated in peripheral blood mononuclear cells from mildly ill patients with influenza. Ectopic expression and loss-of-function validation demonstrate the physiological role of ACSL3 in restricting viral proliferation of diverse IAV subtypes (H1N1, H3N2, H3N8) in vitro and in vivo. Mechanistically, ACSL3 potentiates the antiviral unfolded protein response (UPR) by engaging the endoplasmic reticulum (ER) stress sensors IRE1α and PERK, thereby enhancing the IRE1α-XBP1-s driven inflammation and inhibiting the PERK-ATF4-CHOP mediated apoptosis. Conversely, IAV triggers the lysosomal degradation of ACSL3 and thus reprograms UPR to promote an immunologically silent apoptosis for viral egress and dissemination. Our findings establish ACSL3 as a molecular switch balancing the UPR-mediated antiviral response, and reveal a targeted viral evasion strategy in the virus-host interplay.