Abstract Epidemiological and rodent studies suggest an association between vitamin D deficiency and brain disorders. To date, many mechanisms have been proposed to explain the role of vitamin D on brain function. However, no causal relationship between vitamin D deficiency and a specific brain disorder has been established. It is plausible that exposure to an additional insult alters the vulnerability of the brain to vitamin D deficiency. To our knowledge, a limited number of rodent studies have combined the second-hit insult (e.g. inflammation) with adult vitamin D (AVD) deficiency to examine brain outcomes. This review summarized the impact of multiple second-hit exposures on AVD-deficient animal models. AVD deficiency has been shown to impair hippocampal-dependent cognition in several experimental models, suggesting that the hippocampus could be a critical region in measuring the impact of a combined exposure. We suggest that AVD deficiency, coupled with an additional insult, could impair hippocampal-dependent cognition in a range of brain disorders and provide possible avenues for future research.