Propolis (Brazilian green propolis) is a chemically complex resinous substance that is expected to be beneficial to therapy for Alzheimer’s disease (AD). To reveal its beneficial effect on impaired cognition, we first performed three memory-related behavior tasks in mice aged 4 and 12 months: Y-maze task, novel object recognition task, and passive avoidance task. Oral dosages of 300-1000 mg/ kg once daily for 8 weeks, did significantly prevent the cognitive decline in the APP-KI mice aged 4 months, but not 12 months. Consistent with the observations from behavioral tasks, impaired hippocampal long-term potentiation (LTP) was markedly ameliorated in the acute brain slices prepared from the mice that underwent the repeated propolis administration. In addition, increased phosphorylation of CaMKII and AMPAR subunit (GluA1) was simultaneously observed in the CA1 of the mice. Similar to CaMKII activation, the propolis administration also increased CaMKIV and CREB phosphorylation and BDNF production in the CA1 of the mice. Finally, we confirmed that the presence of 30 μg/ mL propolis significantly elevated intracellular Ca²⁺ concentration in Neuro2A cells. These findings suggest that propolis is capable of rescuing the cognitive dysfunction via both upregulated activities of CaMKII and CaMKIV in the CA1 of the APP-KI mice.