Homeless girls are victims of physical, sexual, and psychological abuse more frequently than the rest of the population. Consequently, their well-being is severely affected. Nonetheless, there is little information about this social group which leads to lack of proper care that, in turn, reduces their quality of life. This research was conducted to develop and test a path model of well-being in a group of 240 Mexican homeless girls aged 6–23 years. Anxiety, depression, assertiveness, and emotion regulation strategies were used as predictors of well-being. Findings reveal significant direct effects of depression and functional emotion regulation strategies on well-being. Results also show significant indirect effects of anxiety, assertiveness, and dysfunctional emotion regulation strategies through depression. The fit indices achieved, x²(3)=1.116, p=.773; NFI=.997, RFI=.985, IFI=1.005, TLI=1.026, CFI=1.000, p=.000; RMSEA(90% CI)=.000(.000–.073), p=.889, demonstrate that the model reliably predicts well-being. Thus, the model fit is acceptable. The current study provides unique findings in terms of a path model that highlights anxiety, depression, emotion regulation strategies, and assertiveness as critical indicators for well-being in homeless girls. Hence, it is essential to consider such factors in order to promote well-being in this group, thereby improving their health and quality of life.