The silkworm is a model organism for studying host-pathogen interactions, particularly with BmNPV, a major pathogen causing significant economic losses in sericulture. Here, we identified and functionally characterized the IRE1α-XBP1s signaling axis in silkworms. Knockdown of BmUFBP1, a key regulator of unfolded protein response, significantly reduced BmIRE1α and BmXBP1s expression, impairing the downstream target SEC61α and ultimately suppressing BmNPV proliferation. Inhibition of BmIRE1α promoted host cell apoptosis and reduced viral proliferation, while activation of BmIRE1α enhanced BmNPV proliferation. Furthermore, blocking the retro-translocation of misfolded proteins with Eeyarestatin I exacerbated ER stress and inhibited viral proliferation, whereas the chemical chaperone TUDC rescued viral proliferation in BmIRE1α-knockdown cells. These findings reveal that BmUFBP1 regulates BmNPV proliferation through the BmIRE1α-XBP1s axis, highlighting the critical role of ER protein homeostasis in viral proliferation. This study provides new insights into the molecular mechanisms of silkworm antiviral responses and offers potential strategies for enhancing BmNPV resistance in sericulture.