Children prenatally exposed to tobacco exhibit higher rates of learning and emotional-behavioral problems related to worse working memory performance. Brain function, however, among tobacco exposed children while performing a working memory task has not previously been examined. This study compared the brain function of tobacco-exposed (n = 7) and unexposed (n = 11) 12-year-olds during a number N-back working memory task using an event-related functional magnetic resonance imaging (fMRI) design. Prenatal alcohol exposure, neonatal medical problems, environmental risk, and sex were statistically controlled. Tobacco-exposed children showed greater activation in inferior parietal regions, whereas unexposed children showed greater activation in inferior frontal regions. These differences were observed in the context of correct responses, suggesting that exposed and unexposed children use different brain regions and approaches to succeed in working memory tasks. Implications for future research and intervention are discussed.