Hispanics disproportionately reside in underprivileged neighborhoods, lack adequate health care, and accumulate limited economic resources. Despite exposure to many disadvantages, Hispanic-origin persons exhibit physical and mental health profiles that are more favorable than the health profiles of non-Hispanics. Scholars in social sciences and public health posit that stronger orientations toward familial attitudes and practices—often referred to as familism—may explain the Hispanic health advantage. We test this assertion using data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The HCHS/SOL collects detailed information pertaining to migration history, generational status, and family orientation among Hispanics who live in urban areas in the United States. We find compelling evidence that familial attitudes are associated with mental well-being, but there is little indication that familism is linked to physical health. Our results highlight the need for scholars to move away from cultural explanations, and instead emphasize the structural barriers that impede overall well-being among minority populations.