Sex contributes to susceptibility of stress‐elicited disorders. Women are at nearly double the risk for developing symptoms of post‐traumatic stress disorder (PTSD), depression, anxiety disorders, and social anxiety or phobia. Despite the higher prevalence of these stress‐triggered disorders, animal models, including the single prolonged stress (SPS) PTSD rodent model, and novel therapies for them are largely understudied in females. Previous studies in males indicate that neuropeptide Y (NPY) has therapeutic potential for stress‐elicited disorders; however none examine its effects in females. Here, we evaluated behavioral manifestations in terms of depressive‐like behavior, anxiety, social interaction, and episodic‐like memory and changes in gene expression in the noradrenergic system in the brain after SPS in females. In addition, we examined the potential therapeutic effects of NPY for these behavioral impairments. Females were exposed to SPS and were immediately infused with intranasal NPY or vehicle in three separate experiments. (1) Stressed females treated with 150μg NPY or vehicle were compared to unstressed controls on forced swim test (FST) and for levels of expression of several genes in the locus coeruleus (LC) 12 days after SPS exposure. (2) We examined stressed females treated with 300μg NPY or vehicle and unstressed controls on the elevated plus maze (EPM) and LC gene expression 7 days after SPS stressors. (3) We evaluated stressed females treated with 600μg NPY or vehicle and unstressed controls on the open field (OF), novel object recognition (NOR), social interaction (SI), and EPM at 7, 13, 19, and 21 days after SPS stressors, respectively. SPS led to increased depressive‐like behavior on the FST and anxiety‐like behavior on the OF and EPM, as well as impaired social interaction. Following FST, the rats displayed elevated tyrosine hydroxylase (TH), CRHR1 and Y1R mRNA levels in the LC, consistent with increased activation of the noradrenergic system. The expression level of these mRNAs was unchanged following EPM, except for Y1R. A higher dose of intranasal NPY tended to have larger anxiolytic effects than the lower dose, however unlike in previously tested males neither dose was significantly different from vehicle. Intranasal NPY did significantly prevent impaired social interaction, as compared to vehicle. There was no effect of SPS or NPY on impairment of memory on the NOR. The results indicate that SPS appropriately elicits PTSD associated behavior and molecular impairments in females. Intranasal NPY has potential for therapeutic intervention with important sex‐specific differences.Support or Funding InformationU.S. Department of Defense (DOD) Award No. W81XWH‐16‐1‐0016 and New York Medical College (NYMC)/Touro Bridge Funding Program 49‐506.