Cognitive dysfunction is the main feature of diabetic encephalopathy (DE). The effect and mechanism of trichostatin A (TSA) on cognitive function of diabetic mice is not elucidated. Our study revealed the key pathways and vital hubgenes of the effect of TSA on hippocampus of type II diabetic mice, including longevity regulating pathway, peroxisome, ribosome, protein processing in endoplasmic reticulum, insulin signaling pathway, CAT and PRKAA2. As well, GSK-1059615, alisertib and avrainvillamide-analog-6 were suggested to be the promising ancillary intervention drugs for diabetic encephalopathy.