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Activation of the IκB kinase (IKK) complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF‐κB has remained elusive. Here, analysis of IKK‐dependent substrates in CRC cells after UV treatment revealed that phosphorylation of BRD4 by IKK‐α is required for its chromatin‐binding at target genes upon DNA damage. Moreover, IKK‐α induces the NF‐κB‐dependent transcription of the cytokine LIF, leading to STAT3 activation, association with BRD4 and recruitment to specific target genes. IKK‐α abrogation results in defective BRD4 and STAT3 functions and consequently irreparable DNA damage and apoptotic cell death upon different stimuli. Simultaneous inhibition of BRAF‐dependent IKK‐α activity, BRD4, and the JAK/STAT pathway enhanced the therapeutic potential of 5‐fluorouracil combined with irinotecan in CRC cells and is curative in a chemotherapy‐resistant xenograft model. Finally, coordinated expression of LIF and IKK‐α is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKK‐α, BRD4, and JAK/STAT signaling with clinical relevance. Synopsis: IκB kinase‐α (IKK‐α) promotes colorectal cancer (CRC) by enhancing BRAF‐ATM‐mediated DNA damage repair, but additional targets remain elusive. Here, BET family protein BRD4 is identified as a novel IKK‐α substrate, providing chemoresistance by inhibiting apoptosis prior to enhanced DNA damage repair, via STAT3 activation. IKK‐α phosphorylates BRD4 at S1117, dictating BRD4 chromatin binding to STAT3 target genes in human CRC cells.BRD4 S1117 phosphorylation is required for activation of the DNA damage response kinases ATM and Chk1.IKK‐α deficiency precludes STAT3 activation in the presence of a functional JAK/STAT signalosome.Combined JAK/STAT and IKK‐α inhibition potentiates chemotherapy in CRC organoids in vitro and xenografts in vivo.Cytokine LIF mediates JAK/STAT activation by IKK‐α imposing therapeutic resistance.LIF and IKK‐α expression correlates with poor outcome in CRC patients. [ABSTRACT FROM AUTHOR]