<p>The population of migrant and refugee children and adolescents increased in the first two decades of the 21st century in the Americas region. This analysis was conducted with the aim of shedding light on the association between the living conditions of migrant minors in Mexico, one of the main transit countries for migrants in the region, and the evolution of health-related quality of life throughout the migration process. Data were collected on 192 minors aged one year or older in transit to the United States through their caregivers in shelters on Mexico’s northern border, including sociodemographic/socioeconomic information and health-related quality of life information prior to departure and during the period of travel. Differences in the evolution of health-related quality of life between origin and travel were explored for different categories of sociodemographic/socioeconomic variables. Several social groups experienced a greater deterioration in some aspects of health-related quality of life, such as those in more precarious situations at origin and along the route, younger minors, or minors whose primary caregivers identified as Afro-descendants and/or indigenous. Minors who had experienced child abuse in their place of origin and adolescents experienced improvements in certain aspects of their health-related quality of life throughout the journey. Despite the exploratory nature of the analysis, it constitutes a first step in identifying populations of children and adolescents on the move in Mexico who should be prioritized for interventions aimed at promoting their well-being.</p>