Activation of c‐Jun amino‐terminal kinase (JNK) facilitates tumour necrosis factor (TNF)‐induced cell death. The p38 mitogen‐activated protein kinase pathway is induced by TNF stimulation, but it has not been implicated in TNF‐induced cell death. Here, we show that hepatocyte‐specific ablation of p38α in mice results in excessive activation of JNK in the liver after in vivo challenge with bacterial lipopolysaccharide (LPS). Despite increased JNK activity, p38α‐deficient hepatocytes were not sensitive to LPS/TNF toxicity showing that JNK activation was not sufficient to mediate TNF‐induced liver damage. By contrast, LPS injection caused liver failure in mice lacking both p38α and IκB kinase 2 (IKK2) in hepatocytes. Therefore, when combined with partial nuclear factor‐κB inhibition, p38α deficiency sensitizes the liver to cytokine‐induced damage. Collectively, these results reveal a new function of p38α in collaborating with IKK2 to protect the liver from LPS/TNF‐induced failure by controlling JNK activation.