The aim of the study is to analyze the mediating effect of self-esteem on the relationship between perceived discrimination and psychological well-being in South American immigrants in Chile. An analytical, cross sectional, non-experimental design was used. We evaluated 853 Peruvians and Colombians living in the northern cities of Arica, Antofagasta, and Santiago de Chile, the capital located in the center of the country. The instruments used were the Ryff Psychological Well-being Scale, the Rosenberg Self-Esteem Scale and the Perceived Discrimination Scale by Basabe, Paez, Aierdi and Jiménez-Aristizabal. We used the estimation method (RWLS) and polychoric correlation matrices, to estimate the effect size and overall fit of the direct effect models of discrimination and self-esteem on psychological well-being, and indirect and total effects of discrimination mediated by self-esteem. While both populations reported similar levels of perceived discrimination, it was found that the means in psychological well-being and self-esteem of the Colombian population were significantly higher than that of the Peruvian population. Regarding self-esteem, the results provided evidence for the possible mediating effect on the relationship between perceived discrimination and psychological well-being. This research aims to contribute to the development of interventions seeking to strengthen self-esteem in order to circumvent possible negative consequences of perceived discrimination, as a consequent, improving immigrants´ personal resources to successfully cope with the diverse demands of their new context.