Memory is stored on the basis of the strength of synaptic connections between neurons in neural circuits. The basics of learning and memory are to alter such strength based on experience. The induction of Long term potentiation (LTP) requires the firing of presynaptic cells, which leads to depolarized postsynaptic cells and the release of neurotransmitters. Coincident activation of the pre- and postsynaptic neurons with NMDA receptors can induce LTP. We have learned from our previous study that entorhinal CCK neurons play a critical role in neocortical memory encoding. In other words, CCK presentation in the neocortex can strengthen synaptic connections locally. However, it is not clear whether CCK can enable the establishment of associative memory, and the underlying mechanism is elusive. Here, we demonstrated in male rodents that, under anesthesia, the visuoauditory association could be created in the presence of CCK, which guided animals’ behavior in a two-choice auditory task. We then examined how neurons responded to the associated AS or VS and what neuron types were involved in sound-to-sound and visuoauditory associations using optogenetics. High-frequency stimulation of the axon terminal of entorhinal CCK neurons in the auditory cortex enabled LTP of the auditory response and visual response in the auditory cortex. This enhanced neuronal response to VS during pairing could be reflected in the subsequent behavioral experiments. We also verified that CCK is critical for the establishment of cross-modal associative memory. The application of CCKBR antagonists could block the establishment of the association, and CCK4 administration could rescue the deficit in CCK-KO mice. We then confirmed that direct inputs from the entorhinal CCK neurons enabled the above neural plasticity in the auditory cortex, and this CCK-dependent LTP was regulated by the NR2A subunit of NMDARs. Finally, we examined the relationship between NMDARs and CCK in neocortical LTP induction. In summary, our findings suggested that the CCK-enabled visuoauditory association during anesthesia can be translated to the subsequent behavior action, and the NR2A subunit was involved in the processing of CCK release. Moreover, we demonstrated an entorhinal-neocortical circuit underlying such neural plasticity, which will help in gaining an understanding of the mechanism of memory formation and retrieval in the brain. Our study can also provide insight into the role of CCK in the pathophysiology and treatment of neuroplasticity disorders.