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Stress-related psychiatric disorders are increasingly common conditions that are notoriously difficult to treat. Identifying the factors that increase the risk of these conditions and defining the biological mechanisms through which they promote the development of these disorders could inform disease pathophysiology and reveal novel therapeutic strategies to improve mental health. Clinical findings suggest that oral antibiotics increase the risk of depression and anxiety, but preclinical studies have had mixed results. Administering antibiotics to rodents has been reported to induce depression- or anxiety-like behavior in some studies but to protect against stress-induced increases in depression- and anxiety-like behavior in others. The reasons for these discrepancies are unclear. The current study examined the effects of antibiotics on stress susceptibility in a model of sub-chronic stress in male and female c57BL/6 mice. Following exposure to oral antibiotics and/or stress, mice were tested in a panel of behavioral assays prior to their brains being examined for potential changes in hippocampal neurogenesis and microglial number. Overall, our results indicate that antibiotics increased susceptibility to stress in several assays, and some of these effects were more pronounced in females than males. Exposure to antibiotics also reduced the proliferation of progenitor cells in the hippocampus of unstressed, but not stressed, animals of both sexes but did not significantly impact the number of microglia or immature neurons in the hippocampus. Future work should examine additional potential mechanisms through which antibiotics impact stress susceptibility and behavior in males and females.