Alcohol and opioid use disorders (AUD, OUD) are prevalent public health issues in the United States, with millions of men and women currently diagnosed. Unfortunately, most preclinical studies of addictive-like behaviors have been conducted using only male subjects. Given the extensive epidemiological data suggesting a sex difference in the progression and manifestation of AUD and OUD, an increased number of studies assessing addictive-like behaviors in female subjects is greatly needed. Therefore, the goals of our current studies were to characterize sex differences in compulsive-like ethanol consumption using the aversion-resistant ethanol intake model, identify the neuroanatomical loci differentially activated in males and females during this behavior, and to establish a model of oral oxycodone self-administration while characterizing sex differences in oxycodone-seeking. We found that female mice exhibit aversion-resistant ethanol intake to a higher degree than males and that this effect does not differ throughout the progression of the estrous cycle. We also observed increased neuronal activation within the ventral tegmental area (VTA) and posterior insular cortex (PIC) of males, but not females, during consumption of quinine-adulterated ethanol, suggesting the potential involvement of these regions in sex differences in quinine-ethanol intake. We also demonstrated that females self-administer significantly more oral oxycodone than males and that this behavior is unaffected by estrous cycle phase. Additionally, both males and females reinstate strongly to oxycodone-seeking following stress exposure, and this behavior is significantly attenuated following systemic treatment with a neurokinin-1 receptor antagonist. Collectively, these findings identified significant sex differences in compulsive-like ethanol intake and in oral oxycodone self-administration. Interestingly, these behaviors are unaffected by fluctuating levels of systemic sex hormones, suggesting that the presence of threshold levels of circulating estradiol or progesterone and/or developmental effects contribute to these sex differences.