NF‐κB is constitutively activated in most human pancreatic adenocarcinoma, which is a deadly malignancy with a 5‐year survival rate of about 5%. In this work, we investigate whether microRNAs (miRNAs) contribute to NF‐κB activation in pancreatic cancer. We demonstrate that miR‐301a down‐regulates NF‐κB‐repressing factor (Nkrf) and elevates NF‐κB activation. As NF‐κB promotes the transcription of miR‐301a, our results support a positive feedback loop as a mechanism for persistent NF‐κB activation, in which miR‐301a represses Nkrf to elevate NF‐κB activity, which in turn promotes miR‐301a transcription. Nkrf was found down‐regulated and miR‐301a up‐regulated in human pancreatic adenocarcinoma tissues. Moreover, miR‐301a inhibition or Nkrf up‐regulation in pancreatic cancer cells led to reduced NF‐κB target gene expression and attenuated xenograft tumour growth, indicating that miR‐301a overexpression contributes to NF‐κB activation. Revealing this novel mechanism of NF‐κB activation by an miRNA offers new avenues for therapeutic interventions against pancreatic cancer.