Anesthesia/surgery could be associated with cognitive impairment and Alzheimer's disease neuropathogenesis. However, whether surgery under different anesthetics has different effects on cognitive function remains largely unknown. We therefore set out to compare effects of anesthetic isoflurane or desflurane plus surgery on cognitive function and hippocampus levels of synaptic marker (postsynaptic density-95 and synaptophysin) and ATP. Five-month-old AD Transgenic (Tg) (FAD5X) and wild-type male mice received isoflurane or desflurane plus abdominal surgery. We assessed cognitive function in Barnes maze and measured hippocampus levels of postsynaptic density-95, synaptophysin, and ATP in the mice. We determined whether vitamin K2 could mitigate these anesthesia/surgery-induced changes. Isoflurane, but not desflurane, plus surgery increased escape latency and escape distance in Barnes maze probe test and reduced postsynaptic density-95, synaptophysin, and ATP levels as compared to control condition in AD Tg mice. Vitamin K2 attenuated the anesthesia/surgery-induced changes in the AD Tg mice. These findings suggest that isoflurane, but not desflurane, plus surgery might induce cognitive impairment via causing brain energy deficits. Pending confirmative studies in both animals and humans suggest desflurane could be a better choice for AD patients when surgery is needed. Moreover, vitamin K2 could treat cognitive deficiency associated with anesthesia and surgery.