Polyp bail-out is a stress response exhibited by some pocilloporid corals with mechanisms and consequences distinct from those of bleaching. Although induction of polyp bail-out has been demonstrated in the laboratory, molecular mechanisms underlying this response have rarely been discussed. We conducted genetic analyses of Pocillopora acuta during initiation of hyperosmosis-induced polyp bail-out, using both transcriptomic and qPCR techniques. Beyond upregulation of apoptosis and genes related to extracellular matrix (ECM) degradation, corals showed significant activation of tumor necrosis factor and fibroblast growth factor (FGF) signaling pathways throughout a 24-h polyp bail-out induction experiment. A common gene expression profile was found between the FAS and CASP8 genes, which reached their expression peaks at 12 h, whereas a different profile showing significant upregulation up to 18 h was displayed by ECM-degrading proteases and genes in the FGF signaling pathway. These results suggest parallel involvement of an extrinsic apoptotic signaling pathway and FGF-mediated ECM degradation in polyp bail-out. Furthermore, in XIAP, JNK, and NFKB1 genes, we detected a third expression profile showing linear upregulation throughout the 24-h experiment period, indicating activation of anti-apoptotic and cell survival signals during polyp bail-out. Our results provide new insights into signaling pathways inducing polyp bail-out and suggest the feasibility of inducing bail-out by specifically triggering these pathways without exerting lethal stresses on the corals.. This will enable acquisition of viable polyps for possible use in coral reef restoration and in coral research.