Helicobacter pylori‐initiated chronic gastritis is characterized by the cag pathogenicity island‐dependent upregulation of proinflammatory cytokines, which is largely mediated by the transcription factor nuclear factor (NF)‐κB. However, the cag pathogenicity island‐encoded proteins and cellular signalling molecules that are involved in H. pylori‐induced NF‐κB activation and inflammatory response remain unclear. Here, we show that H. pylori virulence factor CagA and host protein transforming growth factor‐β‐activated kinase 1 (TAK1) are essential for H. pylori‐induced activation of NF‐κB. CagA physically associates with TAK1 and enhances its activity and TAK1‐induced NF‐κB activation through the tumour necrosis factor receptor‐associated factor 6‐mediated, Lys 63‐linked ubiquitination of TAK1. These findings show that polyubiquitination of TAK1 regulates the activation of NF‐κB, which in turn is used by H. pylori CagA for the H. pylori‐induced inflammatory response.