Chronic psychosocial stress is a recognized, yet understudied risk factor for heart disease, with potential sex-specific effects. We investigated whether chronic stress triggers sex-dependent cardiac dysfunction in isolated Wistar rat hearts subjected to ischemia-reperfusion injury. The experimental cohort underwent 1 hour of daily restraint stress for four weeks versus matched controls, followed by euthanasia (sodium pentobarbitone) and heart excision for ex vivo perfusion. Blood analysis revealed sex-specific alterations in stress hormones and inflammatory markers. Compared to controls, chronic restraint stress (CRS) males displayed decreased plasma brain-derived neurotrophic factor (BDNF) levels (p<0.05), while CRS females exhibited elevated plasma adrenocorticotropic hormone (ACTH) (p<0.01) and reduced corticosterone (p<0.001) alongside lower serum estradiol (p<0.001) and estradiol/ progesterone ratio (p<0.01). Of note, CRS females showed increased serum cardiac troponin T (p<0.05) and tumor necrosis factor-alpha (TNF-a) (p<0.01) with suppressed interleukin (IL)-1a, IL-1β, IL-6, and IL-10 levels (p<0.05) when compared to controls. Ex vivo Langendorff perfusions revealed that CRS female hearts displayed impaired post-ischemic functional recovery for baseline stroke volume (p<0.01), work performance (p<0.05), aortic output (p<0.05), coronary flow (p<0.01), and overall cardiac output (p<0.01) when compared to matched controls and CRS males (p<0.05). Our findings reveal intriguing sex-specific responses at both the systemic and functional levels in stressed hearts. Here, the dysregulation of stress hormones, pro-inflammatory state, and potential underlying cardiomyopathy in females following the stress protocol renders them more prone to damage following myocardial ischemia. This study emphasizes the importance of incorporating sex as a biological variable in cardiac research focusing on stress-related cardiomyopathy.