Epicatechin (EC) was used in this study to antagonize the cognitive dysfunction caused by lead (Pb) exposure in mice. Eight-week-old male Kunming mice were treated with PbCl₂ (20 mg/kg) and/or EC (50 mg/kg) by gavage administration for 4 weeks. Morris water maze test showed that EC could improve memory dysfunction induced by Pb. EC antagonized Ca²⁺ overload, activated Nrf2 signaling pathway and reduced the accumulation of Pb in the brain and serum, which suggested that EC might alter Pb distribution in mice. In vitro, spectroscopic analysis, potentiometric titration and docking studies were applied to inquiry into the interaction between bovine serum albumin (BSA) and Pb²⁺ in presence or absence of EC. EC was proved to chelate Pb²⁺ and reduced the interaction between BSA and Pb²⁺. In summary, EC might protect Pb-induced cognitive impairment by activating Nrf2 signaling pathway, and suppressing Pb accumulation via interference on the binding of Pb to albumin.