The initiative for research in women’s health and sex-based biology has become an important focus of interest over the past 25 years. Epidemiological studies indicate that women are disproportionately at greater risk for anxiety and depressive disorders than men. In addition, women are also are at risk for developing cognitive impairments (e.g., verbal memory decline, decreased cognitive processing, and Alzheimer’s disease) later in life. Estradiol (E2) is the most abundant and prominent estrogen in premenopausal women and its deficiencies during various stages of the reproductive cycle are linked to mood and changes in cognitive performance. E2 modulates mood and cognition via interaction with estrogen receptors (ER) in key brain regions (e.g. prefrontal cortex, hippocampus, and amygdala). The medial amygdaloid nucleus (MeA) is a sexually dimorphic region that is known to mediate fear and stress responses, arousal, and affiliative behaviors in rodents. While it is clear that the MeA regulates certain aspects of emotionality and cognition (social recognition memory), the role of E2 signaling in the MeA on these behavioral endpoints in nonsocial and social settings has not been fully elucidated in females. The goal of the present study was to do an in-depth behavioral assessment of the impact of estradiol signaling, specifically in the MeA, on emotionality and cognition using both nonsocial and social behavioral assays. We accomplished this goal using adult ovariectomized females with bilateral E2 or cholesterol micropellets aimed at the MeA. Following recovery from surgery, females were exposed to a battery of behavioral tasks designed to gauge different aspects of anxiety-like, depression- like and cognitive behaviors including the open field, novel object recognition, social preference/recognition, social interaction and forced swim tests. We tested the following hypotheses in ovariectomized female rats, (1) E2 signaling in the MeA will attenuate anxiety-like and depression-like behaviors in nonsocial and social settings; (2) E2 signaling in the MeA will enhance cognition in social, but not nonsocial settings; (3) E2 signaling in the MeA will decrease cellular activation in mood-related or stress excitatory brain regions. Consistent with our hypothesis, E2 treatment decreased anxiety-like and depression-like behaviors in the open field and forced swim tests, respectively. In addition, E2 treatment decreased cellular activation in some mood regulatory brain regions (i.e., basolateral amygdala, medial amygdala), but not in stress-related areas (paraventricular nucleus of the hypothalamus). E2 signaling in the MeA did not enhance cognitive performance in the social preference recognition or novel objection recognition tests but may have reduced novel object discrimination efficiency. Although, E2 decreased depression-like and anxiety-like behaviors in nonsocial tasks, it increased aggression and decreased sociability towards female conspecifics in social based assays. These findings suggest that E2 modulates emotionality in a context-dependent fashion. Taken together, these data highlight the MeA as an integral brain region for the E2 mediated effects on emotionality and social-sexual behavior in females. Future studies plan to investigate the effects of E2 in the MeA on social-sexual behavior using male conspecifics.