IKKβ, an essential kinase of NF-κB signaling, is composed of an N-terminal kinase domain (KD) and a C-terminal scaffolding domain, containing a ubiquitin-like domain (ULD). The Hsp90 chaperon has special responsibility for folding of protein kinases including IKKβ. Here, we found that Hsp90 inhibition induced IKKβ degradation, which is partially mediated by Keap1. Geldanamycin (GA), a Hsp90 inhibitor, enhances association of IKKβ with Keap1 through the binding site in KD, and translocates IKKβ to detergent-insoluble fractions leading to its autophagic degradation. An electrophile tBHQ suppressed Keap1-mediated proteasomal Nrf2 degradation but not autophagic IKKβ degradation. Substitution mutation of Leu353 to Ala in the ULD destabilizes IKKβ, enhances its association with Keap1, translocates it to detergent-insoluble fractions, and causes its autophagic degradation. These results suggest that Keap1 is involved in the degradation of structural destabilized IKKβ and negative regulation of NF-κB under proteotoxic stress.