Background: Web-based social networks are a powerful communicative element and their use is increasingly widespread. Persons living in extreme social exclusion such as individuals experiencing homelessness can benefit from the positive elements of communication and relationship associated with social networking sites. Objective: This study aimed to suggest the comparison of a Facebook training course and an office software course and their effect on psychological well-being in a group of individuals experiencing homelessness. Methods: An experimental and longitudinal study was designed. Individuals experiencing homelessness were randomly assigned to either the Facebook group or the office software group, and their social skills, self-esteem, self-efficacy, and satisfaction with life were measured on 4 occasions: pretest, at the end of the training course, 1 month later, and 3 months later. A mixed analysis of variance of repeated measures (2×4) was performed. Results: A total of 92 individuals experiencing homelessness participated in the study. The number of cases in which the 4 measurements were completed was 71 (35 in the intervention group and 36 in the control group). The mixed analysis of variance of repeated measures and the multiple regression analysis indicated a significant increase of the 4 analyzed parameters, with greater significance in the areas of social skills and self-esteem. The critical levels associated to the interaction Time×Program were significant in all variables and levels. Therefore, the scores in the 4 analyzed constructs were not equal according to the program carried out throughout the work. The effect size associated to the interaction Time×Program in the social skills scores was large (η2 =0.32); in the self-esteem and self-efficacy scores, it was medium, (η2 =0.13); and in the satisfaction with life scores,it was small (η2 =0.09). The results of the adjustment of the different models of multiple linear regression indicate that the number of hours devoted weekly to the use of Facebook was a predictor of the increase in the scores of social skills (B=3.43, r 2 =.405) and self-esteem (B=.382). Age (B=.175) and self-efficacy (B=.09) were also variables, which with independence and in equal conditions, predicted self-esteem (r2 =.29). Finally, self-esteem (B=.69) was also a predictor variable of the increase of satisfaction with life (r2 =.195). Conclusions: These findings suggest that Facebook could be a key element in homeless psychological well-being and socialization.