Though important for a variety of medical procedures, general anesthesia is not a problem free. Some anesthetics have been suggested to affect a number of signals, which are associated with memory consolidation and cognition. In the present study, we attempted to investigate the molecular mechanism of anesthesia-regulated processes. We found that under hypothermic condition, anesthetic of isoflurane enhances various signals expression in hippocampus, including Hspd1, Actb, Mgst1, THBS4, Syp, C1QC, Serpine, Plat, and Ngf, which were related to cellular stress, neural plasticity responses, and hippocampal injury. Importantly, isoflurane and propofol anesthesia reduced fibroblast growth factor (FGF2) and activity-regulated cytoskeleton-associated protein (Arc) expressions, enhanced glial fibrillary acidic protein (GFAP), Iba1 and phosphorylated-Eukaryotic elongation factor 2 (eEF2) levels as well as down-regulated mitogen-activated protein kinases (MAPKs) family members, including p38, ERK1/2 and JNK, in the hippocampus of animals. Moreover, the in vivo cold water swimming (CWS) experiment and in vitro hypothermic incubation of cells further confirmed our hypothesis that hypothermia is tightly linked to the reduction of FGF2 and Arc, augment of GFAP, Iba1 and p-eEF2, and the decreasing of MAPKs. Generally, our study provided new insights into the modulation of various signals by anesthesia-triggered hypothermia.