<p>The neuroprotective effects of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) have been reported in experimental models of central nervous system (CNS) disorders due to its multi-target actions. Considering the limited efficacy of current treatments for post-traumatic stress disorder (PTSD), this study aimed to investigate the anti-PTSD-like effects of 4-PSQ and its underlying mechanisms during the early developmental stage of single prolonged stress (SPS)-induced PTSD in male and female mice. Following 4&#xa0;h to the SPS exposure, mice were treated with 4-PSQ (5&#xa0;mg&#xa0;kg⁻¹) or vehicle by the intragastric (i.g.) route for three days. The open field test, the elevated plus maze test, and the contextual fear conditioning were performed on days 2 and 3 of the experimental protocol. A short treatment with 4-PSQ reversed the anxiety-like phenotype and the fear memory strength induced by SPS in mice of both sexes. Elevated levels of reactive species (RS) in the cerebral cortex, hippocampus, and hypothalamus of SPS-exposed mice were attenuated by 4-PSQ. Concerning the antioxidant system, males and females exposed to SPS displayed distinct patterns of thiol non-protein (NPSH) levels and the catalase (CAT) activity in the CNS. Notably, the SPS-induced fear memory strength was found to be negatively correlated with Na⁺, K⁺-ATPase inhibition and positively correlated with AChE enhancement, underscoring the relevance of both enzymes in the pathogenesis of PTSD. The 4-PSQ treatment normalized both Na⁺, K⁺-ATPase and AChE activities. In Summary, the 4-PSQ attenuated the behavioral and sex-specific mechanisms in response to SPS and may be considered as promising molecule for PTSD treatment.</p> Graphical abstract <p></p>