Aim To identify alteration in key molecular components related to memory formation and insulin signaling in the hippocampus after rosiglitazone was in-jected into the ob/ob mice to test whether cognitive dysfunction was pharmacologically reversed by regula-tion of rosiglitazone. Methods The age-matched mice were divided into three groups ( n=18 ): Saline-trea-ted WT mice ( WT-Saline);Saline-treated ob/ob mice ( ob/ob-Saline) and RSG-treated ob/ob mice ( ob/ob-RSG) through intraperitoneal injection of rosiglitazone ( RSG) . The random glucose levels were measured for 10 days during the intraperitoneal injection period. No-vel object recognition was performed before mice were sacrificed. Western blot was implemented to evaluate the following proteins: BACE1, p-Tau, p-IRS1,IRS1, p-Akt and Akt in hippocampal tissues. The Aβ1-40 levels were detected by ELISA Kit. Results The random blood glucose levels were significantly re-duced in ob/ob-RSG compared with ob/ob-saline. RSG treatment led to an increase in hippocampus-de-pendent cognition of ob/ob mice according to the novel object recognition. The proteins levels of BACE1, p-Tau and Aβ were lowered in RSG-treated ob/ob mice. Furthermore, RSG treatment up-regulated hippocampal p-IRS1/IRS1 and p-Akt/Akt ratio. Conclusion Ros-iglitazone ameliorates cognitive deficits in ob/ob mice through up-regulating insulin signaling pathways in the hippocampus.