Nrf2 (NF-E2-related factor-2) is a transcription factor that regulates oxidative/xenobiotic stress responses and represses inflammation. However, the mechanisms by which Nrf2 alleviates inflammation are not fully understood. This study demonstrates that Nrf2 inhibits the transcriptional upregulation of proinflammatory cytokines, such as IL-6 and IL-1β, induced by lipopolysaccharide (LPS) in macrophages. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes and inhibits RNA Polymerase II (Pol II) recruitment. The Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species (ROS) levels. Murine inflammatory models further showed that Nrf2 interferes with *IL6* induction and inflammatory phenotypes *in vivo*. These findings indicate that Nrf2 opposes the transcriptional upregulation of proinflammatory cytokine genes and identifies Nrf2 as an upstream regulator of cytokine production, providing a molecular basis for an Nrf2-mediated anti-inflammatory approach.Nrf2 (NF-E2-related factor-2) is a transcription factor that regulates oxidative/xenobiotic stress responses and represses inflammation. However, the mechanisms by which Nrf2 alleviates inflammation are not fully understood. This study demonstrates that Nrf2 inhibits the transcriptional upregulation of proinflammatory cytokines, such as IL-6 and IL-1β, induced by lipopolysaccharide (LPS) in macrophages. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes and inhibits RNA Polymerase II (Pol II) recruitment. The Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species (ROS) levels. Murine inflammatory models further showed that Nrf2 interferes with *IL6* induction and inflammatory phenotypes *in vivo*. These findings indicate that Nrf2 opposes the transcriptional upregulation of proinflammatory cytokine genes and identifies Nrf2 as an upstream regulator of cytokine production, providing a molecular basis for an Nrf2-mediated anti-inflammatory approach.