This review explores the complex molecular interactions between the Nrf2 and NF-κB pathways, which are crucial for regulating cellular responses to oxidative stress and inflammation. Nrf2, a key transcription factor, mediates the expression of phase II antioxidant proteins to protect cells from reactive oxygen species (ROS). NF-κB, a family of transcription factors, plays a central role in immune responses, inflammation, and cell proliferation. The review highlights how the absence of Nrf2 can exacerbate NF-κB activity, leading to increased cytokine production, and how NF-κB can modulate Nrf2 activity, affecting target gene expression. Key mechanisms include the interaction between Nrf2 and Keap1, which regulates Nrf2 stability, and the competition between Nrf2 and p65 for the transcriptional co-activator CBP. The review also discusses the importance of these pathways in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Parkinson’s disease (PD), and the potential of Nrf2-inducing compounds to reduce inflammation and improve disease outcomes.This review explores the complex molecular interactions between the Nrf2 and NF-κB pathways, which are crucial for regulating cellular responses to oxidative stress and inflammation. Nrf2, a key transcription factor, mediates the expression of phase II antioxidant proteins to protect cells from reactive oxygen species (ROS). NF-κB, a family of transcription factors, plays a central role in immune responses, inflammation, and cell proliferation. The review highlights how the absence of Nrf2 can exacerbate NF-κB activity, leading to increased cytokine production, and how NF-κB can modulate Nrf2 activity, affecting target gene expression. Key mechanisms include the interaction between Nrf2 and Keap1, which regulates Nrf2 stability, and the competition between Nrf2 and p65 for the transcriptional co-activator CBP. The review also discusses the importance of these pathways in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Parkinson’s disease (PD), and the potential of Nrf2-inducing compounds to reduce inflammation and improve disease outcomes.