Changes in living arrangements (from living with, or not living with family) may affect the health-related quality of life (HRQoL). This study aimed to investigate the impact of living arrangement on HRQoL among adolescents migrating from rural to urban schools, and whether social support, in addition to living with a family, had an impact. A cross-sectional survey of 459 school adolescents was carried out in two public schools in Guyuan County, Ningxia Hui Autonomous Region, China in 2015. The survey contained the following questionnaires: a self-designed questionnaire, the 12-item Short Form Health Survey (SF-12), and the Social Support Rating Scale (SSRS). Of the 459 adolescents sampled (aged 15.41 ± 1.07 years with range of 13 to 18), 61.7% were living with family, and 38.3% were not living with family. Those students not living with families had lower Mental Component Scale (MCS) scores as well as less social support overall. Those students, who were not living with families, also reported more chronic health problems and more alcohol consumption compared to those students living with families. Social support was a statistically significant mediating factor on the effect of living arrangements on MCS. Our findings demonstrated that those students, who were not living with families, tended to have more health-related quality of life issues, but social support partially mediated the relationship between living arrangements and health.