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Objective: Negative consequences of childhood maltreatment have been well-documented, including poorer executive functioning and nonverbal reasoning in midlife. However, not all adults with a history of childhood maltreatment manifest these outcomes, suggesting the presence of risk and protective factors. Based on growing empirical support for the importance of social variables in understanding neuropsychological development and functioning, we examined whether social support and social isolation mediate or moderate the effects of childhood maltreatment on cognitive functioning in midlife. Method: In the context of a prospective cohort design study, individuals with documented histories of childhood maltreatment (ages 0–11 years) and demographically matched controls were followed up and interviewed in adulthood. Social support and isolation were assessed in young adulthood (Mage = 29), and cognitive functioning was assessed in midlife (Mage = 41). Structural equation modeling was used for mediation and linear regressions for moderation. Results: Childhood maltreatment predicted higher levels of social isolation and lower levels of social support and cognitive functioning. Only social isolation mediated the relationship between childhood maltreatment and midlife cognitive functioning, whereas childhood maltreatment interacted with social support to predict Matrix Reasoning in midlife. Social support was protective for the control group but not for those maltreated. Conclusions: Social isolation and social support play different roles in understanding how childhood maltreatment impacts midlife cognitive functioning. Greater social isolation predicts greater deficits in cognitive functioning overall, whereas the protective effects of social support are limited to those without a documented history of childhood maltreatment. Clinical implications are discussed.