Chronic inflammation is known to promote cancer, suggesting that negative regulation of inflammation is likely to be tumor suppressive. We found that p53 is a general inhibitor of inflammation that acts as an antagonist of nuclear factor κB (NFκB). We first observed striking similarities in global gene expression profiles in human prostate cancer cells LNCaP transduced with p53 inhibitory genetic element or treated with TNF, suggesting that p53 inhibits transcription of TNF‐inducible genes that are largely regulated by NFκB. Consistently, ectopically expressed p53 acts as an inhibitor of transcription of NFκB‐dependent promoters. Furthermore, suppression of inflammatory response by p53 was observed in vivo in mice by comparing wild‐type and p53 null animals at molecular (inhibition of transcription of genes encoding cytokines and chemokines, reducing accumulation of reactive oxygen species and protein oxidation products), cellular (activation of macrophages and neutrophil clearance) and organismal (high levels of metabolic markers of inflammation in tissues of p53‐deficient mice and their hypersensitivity to LPS) levels. These observations indicate that p53, acting through suppression of NFκB, plays the role of a general “buffer” of innate immune response in vivo that is well consistent with its tumor suppressor function and frequent constitutive activation of NFκB in tumors.