The hypothesis that people respond to reminders of mortality with closed-minded, ethnocentric attitudes has received extensive empirical support, largely from research in the Terror Management Theory (TMT) tradition. However, the basic motivational and neural processes that underlie this effect remain largely hypothetical. According to recent neuropsychological theorizing, mortality salience (MS) effects on cultural closed-mindedness may be mediated by activity in the behavioral inhibition system (BIS), which leads to passive avoidance and decreased approach motivation. This should be especially true for people motivated to avoid unfamiliar and potentially threatening stimuli as reflected in a high need for closure (NFC). In two studies involving moderated mediation analyses, people high on trait NFC responded to MS with increased BIS activity (as indicated by EEG and the line bisection task), which is characteristic of inhibited approach motivation. BIS activity, in turn, predicted a reluctance to explore foreign cultures (Study 1) and generalized ethnocentric attitudes (Study 2). In a third study, inhibition was induced directly and caused an increase in ethnocentrism for people high on NFC. Moreover, the effect of the inhibition manipulation × NFC interaction on ethnocentrism was explained by increases in BIS-related affect (i.e., anxious inhibition) at high NFC. To our knowledge, this research is the first to establish an empirical link between very basic, neurally-instantiated inhibitory processes and rather complex, higher-order manifestations of intergroup negativity in response to MS. Our findings contribute to a fuller understanding of the cultural worldview defense phenomenon by illuminating the motivational underpinnings of cultural closed-mindedness in the wake of existential threat.