Background: Sertraline is one of the several drugs approved for posttraumatic stress disorder (PTSD). The hippocampal CA1 region is known to be associated with anxiety. Single-prolonged stress (SPS)-treated rats, a rodent model of PTSD, has been found to induce apoptosis of hippocampal pyramidal neurons but the effect of sertraline on anxiety-like behaviors and hippocampal CA1 neurons had not been studied on it. The aim of this study was to investigate the effect of sertraline on classical and ethological variables of anxiety-like behavior, and histomorphological appearance of the hippocampal CA1 region in SPS-induced rats. Methods: Wistar male rats (8-10 weeks; 150-180 g [n = 35]), were randomized into 5 groups. Sertraline was administered for 14 days. Behavioral measures were studied with elevated plus maze test. Hippocampus-containing coronal slices of the brains were HE-stained and analyzed using Optilab. Results: The numbers of closed arm entries and stretched-attend posture (SAP) were not different between groups. Sertraline decreased time spent in closed arms, increased open arm entries, time spent in open arms, and unprotected head dips (UHD). The lowest dose of sertraline exerted the highest level of anxiety as evidenced by the number of protected head dips (PHD), but higher doses ameliorated this effect. The spatial arrangement of CA1 pyramidal neurons was severely impaired in all SPS-exposed groups. Pyknotic, dark-stained, and shrunk neurons were commonly found in sertraline-treated rats, especially at the dose of 18 mg/kg/day. Conclusions: We found that chronic administration of sertraline exerts an anxiolytic effect on single-prolonged stress-induced rats with increased â€œchaoticâ€ appearance in histomorphology as the dose increased.