Objective To investigate the effect of phospholated-ERK1/2 on NF-κB p65 expression in the substania nigra(SN) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease(PD) . Methods PD mouse model was induced by MPTP and the behavior of mouse was observed. Immunohistochemistry and Western blotting analysis were used to observe the changes in expression of tyrosine hydroxylase (TH), NF-κB p65 and p-ERK1/2 in the SN of midbrain. Meanwhile, the above changes were also observed after treatment with U0126, a specific inhibitor of ERK. Results 1 h after the third MPTP administration, there were much more p-ERK1/2 positive cells than NF-κB p65 positive cells in the SN. 24 h after the fifth injection of MPTP, NF-κB p65 positive cells were significantly increased and p-ERK1/2 positive cells were decreased, accompanied by marked loss of TH positive neurons. The above changes were greatly alleviated in animals treated with U0126. Conclusion ERK1/2 pathway may regulate NF-κB p65 activation in MPTP-induced mouse model of Parkinson’s disease, which leads to loss of dopamine neurons.