Abrupt cessation of chronic alcohol consumption triggers signaling cascades that harm vulnerable brain regions and produce neurobehavioral deficits. We have demonstrated that a program of intermittent, normobaric hypoxia training (IHT) in rats prevents neurobehavioral impairment resulting from abrupt ethanol withdrawal (EW). Moreover, EW induced expression of stress-activated protein kinase p38 and presenilin 1 (PS1), the -secretase component that produces the neurotoxic amyloid-β (Aβ) peptides, Aβ40 and Aβ42. We tested the hypotheses that (1) IHT limits EW-induced activation of the p38-PS1 axis, thereby attenuating -secretase activation and Aβ accumulation, and (2) EW disables heat shock protein 25 (HSP25), a p38 substrate, molecular chaperone and antioxidant, and provokes protein carbonylation in a manner suppressed by IHT. Adult male rats completed two cycles of 4 wk ethanol diet (0 or 6.5% w/v) and 3 wk EW. A 20 d IHT program of cyclic, 5-8 min exposures to 9.5-10% FIO₂ was administered during the first EW phase. PS1, phosphorylated p38 (P-p38) and HSP25 were analyzed by immunoblot, PS1 messenger RNA by quantitative polymerase chain reaction, protein carbonyl content by spectrometry, and Aβ40 and Aβ42 contents by enzyme-linked immunosorbent assay, in prefrontal cortical extracts. IHT attenuated the EW-associated increases in PS1, P-p38, Aβ40, Aβ42 and protein carbonyl contents, but not that of PS1 messenger RNA, while preserving functionally competent HSP25 dimers in EW rats. Collectively, these findings demonstrate that IHT attenuates EW-activation of the p38-PS1--secretase axis, thereby dampening Aβ accumulation, and prevents EW-induced oxidative protein damage.