The nicotinic acetylcholine receptor (nAChR) has been shown to play a functionally distinct role in the development of the adolescent brain through the modulation of neurotransmitter release across various neurodevelopmental milestones. CHRNA2 encodes for the α2 nicotinic acetylcholine receptor associated with CA1 oriens lacunosum moleculare GABAergic interneurons and is associated with learning and memory. Prior literature consistently supports the finding that chronic nicotine exposure during adolescence leads to an impairment in learning in adulthood. Previously, we found that adolescent male hypersensitive (CHRNA2 L9'S/L9'S) mice had impairments in learning and memory during a pre-exposure-dependent contextual fear conditioning task that could be rescued by low-dose nicotine exposure. In this study, female adolescent CHRNA2 L9'S/L9'S mice and wild-type (WT) littermate controls were exposed to saline or nicotine (0.09 mg/kg) using a hippocampus-dependent task of pre-exposure-dependent contextual fear conditioning. Alterations in freezing behavior—an indication of learning—were compared between CHRNA2 L9'S/L9'S and WT female adolescent mice as well as against adolescent male CHRNA2 L9'S/L9'S and WT mice. We found that nicotine-treated adolescent WT female mice had significantly greater freezing behavior than both saline-treated WT mice and nicotine-treated CHRNA2 L9'S/L9'S female mice. Nicotine-treated adolescent CHRNA2 L9'S/L9'S female mice did not have enhanced freezing behavior on context test (CT) day when compared with saline-treated CHRNA2 L9'S/L9'S female mice. These results indicate that hypersensitivity of the CHRNA2 gene in female adolescent mice produces deficits in nicotine-dependent learning and memory in the hippocampus. These results are contrasted with the results obtained in the previously published male data where we found that male hypersensitive (CHRNA2 L9'S/L9'S) mice had impairments in learning and memory that could be rescued by low-dose nicotine exposure. Thus, nicotine exposure mediates a sexually dimorphic pattern of learning and memory in WT and CHRNA2 L9'S/L9'S adolescent mice exposed to a pre-exposure-dependent contextual fear conditioning paradigm. At present, the mechanism driving sexual dimorphisms between nicotine-exposed adolescent CHRNA2 L9'S/L9'S mice is unknown. Further research must be conducted in both in-vitro and in-vivo studies examining the role of α2- expressing nAChR signaling mediating sex-dependent effects.