The maternal bond is a vital social connection that supports the survival and well-being of both the caregiver and offspring. Disruption of this bond, particularly following offspring loss, can result in profound trauma with long-lasting consequences. While considerable research has focused on the impact of maternal separation on offspring development, the biological effects of offspring loss on the mother remain largely unexplored. In this study, we examined the long-term effects of offspring loss on neuroplasticity, the oxytocin (OXT) and corticotropin-releasing factor (CRF) systems, and stress-coping behaviors in Sprague-Dawley rat mothers. We examined two groups of lactating mothers: (I) a control group, in which dams remained with their pups until natural weaning, and (II) a separated group, in which all offspring were removed on lactation day 1 and the mothers experienced offspring loss until the time corresponding to weaning (19 days). Our results reveal that pup removal increased oxytocin receptor binding–most prominently in the ventromedial hypothalamus (VMH)–and reduced dendritic spine density in this brain region, without altering estrogen receptor α or calbindin cell expression. Separated mothers additionally showed elevated plasma corticosterone levels and increased passive stress-coping behaviors in the forced swim test. Remarkably, passive stress-coping behavior was rescued by central CRF receptor blockade but not by central OXT treatment, indicating that the CRF system plays a critical role in the distress response to offspring loss. These findings establish a novel rat model to investigate the neurobiological consequences of maternal stress following offspring loss.