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Background Recent preclinical and clinical studies have shed light on the possible impact of sex and oestrous/menstrual cycle on ketamine’s antidepressant action but with incongruous results. The preclinical studies that have shown the effects of ovarian sex hormones have not done so in animal models of depression. Thus, the aim of the present study is to scrutinize the acute behavioural responses to a subanaesthetic dose of S-ketamine in males vs females and in different oestrous phases in free-cycling females in a well-powered translational approach. Methods We evaluated the behavioural sensitivity to 20 mg/kg S-ketamine (i.p.) in male and female Flinders sensitive line (FSL) rats and their counterpart Flinders resistant line (FRL) rats subjected to the open field and forced swim tests. Female rats were disaggregated into different oestrous phases, and the behavioural outcomes were compared. Results Acute administration of S-ketamine had robust antidepressant-like effects in FSL rats. Within our study power, we could not detect sex- or oestrous-cycle-specific different antidepressant-like responses to S-ketamine in FSLs. Fluctuations in the levels of ovarian sex hormones across different oestrous cycles did not behaviourally affect the S-ketamine’s rapid-acting antidepressant mode of action. No sex- or oestrous-cycle-related impact on behavioural despair was observed even among FRLs and saline-treated FSLs. Conclusions We conclude that physiological oscillations of estrogen and progesterone levels neither amplify nor diminish the behavioural antidepressant-like effect of S-ketamine. In addition, fluctuations of ovarian sex hormones do not predispose female animals to exhibit enhanced or reduced depressive- and anxiety-like behaviours.