Background Globally, common psychiatric disorders such as depression and anxiety are among the leading causes of morbidity and mortality. The 12-item General Health Questionnaire (GHQ-12) is a widely used questionnaire for screening or detecting common psychiatric disorders. The purpose of this study was to examine the reliability, construct validity and factor structure of the GHQ-12 in a large sample of African, Asian and South American young adults. Methods A cross-sectional study was conducted among 9077 undergraduate students from Chile, Ethiopia, Peru and Thailand. Students aged 18-35 years were invited to complete a self-administered questionnaire that collected information about lifestyle, demographics, and GHQ-12. In each country, the construct validity and factorial structures of the GHQ-12 questionnaire were tested through exploratory and confirmatory factor analyses (EFA and CFA). Results Overall the GHQ-12 items showed good internal consistency across all countries as reflected by the Cronbach's alpha: Chile (0.86), Ethiopia (0.83), Peru (0.85), and Thailand (0.82). Results from EFA showed that the GHQ-12 had a two-factor solution in Chile, Ethiopia and Thailand, although a three-factor solution was found in Peru. These findings were corroborated by CFA. Indicators of goodness of fit, comparative fit index (CFI), root mean square error of approximation (RMSEA), and standardized root mean squared residual, were all in acceptable ranges across study sites. The CFI values for Chile, Ethiopia, Peru and Thailand were 0.964, 0.951, 0.949, and 0.931, respectively. The corresponding RMSEA values were 0.051, 0.050, 0.059, and 0.059. Conclusion Overall, we documented cross-cultural comparability of the GHQ-12 for assessing common psychiatric disorders such as symptoms of depressive and anxiety disorders among young adults. Although the GHQ-12 is typically used as single-factor questionnaire, the results of our EFA and CFA revealed the multi- dimensionality of the scale. Future studies are needed to further evaluate the specific cut points for assessing each component within the multiple factors.