Lead (Pb), an ancient metallic environmental pollutant, has received widespread attention and has been strictly controlled, but current findings have found the hazards of Pb to be much higher than previously estimated. Pb exposure can lead to memory impairment. However, the underlying molecular mechanisms have not been fully elucidated. Dynamic changes in dendritic spines form the structural basis of memory, and MEF2C, a key regulator of dendritic plasticity, plays an important role in hippocampus-dependent learning and memory. This study focused on the role of ERK-induced MEF2C phosphorylation in Pb-induced learning and memory impairments. A rat model of Pb exposure from the embryo to adolescence and the model of Pb exposure in PC12 cells were established. The results showed that Pb exposure reduced the phosphorylation level of MEF2C in the rat hippocampus by affecting the expression of ERK5. In addition, it reduced the expression of MEF2C at the translation stage, which affected its transcriptional ability and led to abnormal expression of the downstream factor ARC, causing alterations in neuronal dendritic plasticity and affecting its memory ability. Further experiments showed that regulating the phosphorylation level of MEF2C could affect neurite growth in PC12 cells exposed to Pb. Our findings demonstrate that Pb exposure may contribute to memory impairment by affecting MEF2C and its phosphorylation levels, resulting in altered dendritic plasticity.