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 proteolysis, corals showed significant activation of tumor necrosis factor and fibroblast growth factor (FGF) signaling pathways during induction of polyp bail-out. In our qPCR analysis, a common upregulation profile, peaking at 43.0‰ salinity, was found in the FAS and CASP8 genes, whereas a different profile, showing significant upregulation up to 45.0‰, was displayed by matrix metalloproteinases and genes in the FGF signaling pathway. These results suggest parallel involvement of an extrinsic apoptotic signaling pathway and FGF-mediated extracellular matrix degradation in polyp bail-out. Furthermore, in the XIAP, JNK, and NFKB1 genes, we detected a third expression profile showing linear upregulation that becomes maximal at the endpoint salinity level of the experiment (46.0‰), indicating activation of anti-apoptotic and cell survival signals during polyp bail-out. Our results provide new insights into signaling pathways responsible for polyp bail-out and suggest the feasibility of inducing bail-out by specifically triggering these pathways without exerting lethal stresses on the corals, which in turn will facilitate acquisition of viable polyps for possible use in coral reef restoration.