Lead (Pb) is one of the most highly toxic metal pollutant that can cause damage to the immune system. It is known that selenium (Se) can antagonize heavy metals. To explore the toxic effects of Ph poisoning on bird immune cells, as well as the alleviating effects of Se on Pb, Se supplement and/or Pb poisoning chicken models were established. One hundred and eighty Hyline 7-day-old male chickens received either Se (1 mg Se per kg of diet), Pb (350 mg Pb per liter water) or Se +Pb in their diet and water for 90 days. Then, whole blood was collected from the four groups of chickens, and serum and neutrophils were isolated. The levels of Se and Pb in chicken serum, mRNA levels of 24 selenoproteins (GPX1, GPX2, GPX3, GPX4, Diol, Dio2, Dio3, Txnrdl, Txnrd2, Txnrd3, SETS, SPS2, SELK, SELW1, SEP15, SEPX1, SELT, SELL SELO, SELM, SEPN1, SEPP1, SELIJ, SELH) and inflammatory factors (INF-alpha, COX-2, iNOS, NF-kappa B), and iNOS protein level in chicken neutrophils were determined, and protein-protein interaction prediction and principal component analysis were performed. The data showed that Pb exposure increased Pb content in serum, activated the NF-kappa B pathway, and increased the expression of selenoproteins in chicken neutrophils. Se supplements could reduce Pb concentration in serum, had a mitigative effect on the activation of the NF-kappa B pathway and further enhanced the upward trend of selenoprotein expression induced by Pb exposure. These results suggest that Se supplement could eliminate Pb in serum and alleviate the activation of the NF-kappa B pathway under Pb exposure by increasing the expression of selenoproteins.