Many functional aspects of the protein kinase p38α have been illustrated by more than three hundred structures, covering free forms and complexes with activators, substrates and inhibitor compounds. All these structures reveal the p38α protein in reduced forms. Here we report an oxidized conformation showing an intramolecular disulfide bond between the Cys119 and Cys162, conserved in vertebrates, thereby maintaining the kinase in a previously undescribed dormant state. This oxidized state does not affect the conformation of the catalytic site, but alters the docking groove by unwinding and displacing the short αD helix caused by the movement of Cys119 towards Cys162. The transition between the oxidized and reduced conformations provides a mechanism for fine-tuning p38α activity as a function of redox conditions, beyond its activation loop phosphorylation. Moreover, the conformational equilibrium between these redox forms reveals an unexplored cleft for p38α inhibitor design, which we describe in detail.