Studies have shown that ergothioneine (ergo), a derivative of histidine synthesized by certain fungi and actinobacteria, can protect against neuronal injury induced by exogenous Aβ. Our aim is to investigate the role of ergo in synaptic plasticity using the AD mouse model. Field electrophysiology was performed in the CA1 region of hippocampal slices from male C57BL/6 mice to measure synaptic modification over time. Hippocampal slices from the double transgenic AD mouse model APP/PS1, when stimulated with a strong tetanisation protocol, exhibit impaired late long-term potentiation (late-LTP), which is not observed in age-matched healthy mice. However, when the slices were bath-applied with ergo, a rescue effect was observed, exhibiting a persistent late form of LTP (late-LTP). Moreover, a similar rescue effect is observed in synaptic tagging and capture (STC), providing a conceptual basis for transforming short-term memory into long-term memory in a time-dependent manner. Lastly, we utilized both the Morris water maze and the behavioral tagging paradigm to investigate the role of ergo in memory retention and synaptic associativity. Moving forward, we will perform biochemical analysis to ascertain the role of ergo in memory enhancement. These results demonstrate that ergo has a positive modulatory effect on the spatial and associative memory deficits induced by AD. This study provides insights into the therapeutic role of ergo in preventing neurodegenerative diseases.