<p>The normal function of mitochondria plays a key role in innate immunity. Normally, changes in the internal and external environment will lead to mitochondrial stress, and then the body will produce mitochondrial unfolded protein response (UPR^mt) to maintain mitochondrial homeostasis. Ginkgolide A (GA) is a diterpenoid isolated from Ginkgo, which has many important biological activities such as anti-inflammatory, anticancer, anxiolytic-like, anti-antherosclerosis and anti-atherombosis. However, whether GA affects innate immune responses and the underlying molecular mechanisms are still unknown. In the present study, we show that 100 µM GA enhances the resistance to Gram-negative pathogens <i>Pseudomonas aeruginosa</i>, <i>Salmonella enterica</i> and Gram-positive pathogens <i>Staphylococcus aureus</i>, <i>Enterococcus faecalis</i> in <i>Caenorhabditis elegans</i> by clearance intestinal bacterial loads. We also find that GA enhances innate immunity through a homeodomain transcriptional regulator DVE-1, which activates the UPR^mt. Because DVE-1 encodes a homeodomain transcription regulator that is homologous to the mammalian SATB2 transcription factor. Furthermore, we demonstrate that this function was conserved, because GA also manifested protective function in lung epithelial cell and mice during <i>P. aeruginosa</i> infection via the homeodomain transcription factor SATB2. Hence, our research suggests that GA has the potential therapeutic compound to protect patients from pathogen infection.</p>