Psychological research suggests that violent extremism (e.g., terrorism) stems partly from existential motives, such as individuals' need to achieve significance in life after experiencing failure, ostracism, or humiliation (Significance Quest Theory; SQT). Parallel investigations from sociology and criminology established similar findings by linking anomia-a syndrome including feelings of meaninglessness, powerlessness, isolation, self-estrangement, and normlessness-with violent behavior. In line with SQT, this contribution tested if anomia could mediate Loss of Significance effects on violent extremism. Accordingly, three studies conducted in France highlight indirect effects of exposure to discrimination on legitimation of political violence (Study 1, cross-sectional, minority population sample, N = 110), violent behavioral intentions (Study 2, experimental, undergraduate sample, N = 249), and support for ISIS fighters (Study 3, experimental, undergraduate sample, N = 221) through anomia. A subsequent study shows this indirect effect to be robust when controlled for Social Dominance Orientation and Political Extremism (Study 4, cross-sectional, undergraduate sample, N = 279). A final investigation re-analyzing data collected in Turkey highlights a reverse effect when the independent variable tapped into social inclusion (rather than exclusion; Study 5, cross-sectional, undergraduate sample, N = 321). This indirect effect was also robust to Political Extremism and Intolerance as control variables. These results support the usefulness of considering anomia as a proximal predictor of violent extremism in a SQT perspective.