Lead (Pb), one of the pervasive and protracted environmental heavy metals, is believed to affect the female reproductive system in many species. The Nrf2 and NF-kappaB are the two key transcriptional factors regulating cellular redox status and response against stress and inflammation respectively, showing an interaction between each other. The aim of this study is to investigate the effect of Pb on bovine granulosa cells (GCs) and its association with the regulation of Nrf2 and NF-kappaB pathways. For this, bovine GCs were cultured in vitro and exposed to different doses of Pb for 2 h. Cellular response to Pb insult was investigated 24 h post treatment. Results showed that exposure of GCs to Pb-induced ROS accumulation and protein carbonylation. Additionally, GCs exhibited reduction in cell viability and decrease in the expression of cell proliferation marker genes (CCND2 and PCNA). This was accompanied by cell cycle arrest at G0/G1 phase. Moreover, Pb downregulated both Nrf2 and NF-kappaB and their downstream genes. Lead increased the expression of endoplasmic reticulum (ER) stress marker genes (GRP78 and CHOP) and the proapoptotic gene (caspase-3) while the antiapoptotic gene (BCL-2) was reduced. Our findings suggest that Pb-driven oxidative stress affected GCs proliferation, enhances ER stress, induces cell cycle arrest and mediates apoptosis probably via disruption of Nrf2/NF-kappaB cross-talk. However, further functional analysis is required to explain different aspects of Nrf2 and NF-kappaB interactions under metal challenge.