The Latino population is one of the largest immigrant groups in the United States, with the majority being of Mexican descent. Whether immigrating to the US is positive for the well-being of Mexican immigrants and future generations is an important question. We examined how nativity status and quality of life indicators relate to life satisfaction among foreign-born and US-born Mexican descent Latinos living in California. Participants (N = 893) were from the California Quality of Life Survey, a population-based mental health survey of the California population. Multiple regressions examining sociodemographic and indicators of life satisfaction found higher life satisfaction among the foreign-born compared to US-born: (US-born first generation: Wald F = 18.70, < 0.001; US-born second generation and higher: Wald F = 12.09, < 0.001), females (Wald F = 7.05, < 0.01), and individuals reporting more social support (Wald F = 40.20, < 0.001), absence of frequent distress (Wald F = 41.46, < 0.001), and better physical health (Wald F = 15.28, < 0.001). Life satisfaction was lower for US-born Mexicans than for Mexican immigrants. Research, interventions, and policies are needed for mental health equity that address this lack of well-being in US-born Mexican Latinos.