Background: The World Health Organization Quality of Life-BREF (WHOQOL-BREF) has generally been used for patients, few studies in migrants who move from rural to urban within one country. Many studies asserted that social isolation presents a risk to individual health. Poor social networks are associated with worse QOL. This study examined health-related quality of life (HRQOL) and social support in new-generation migrant workers and compared it with urban workers. Methods: Nine hundred thirty new-generation migrant workers and 939 urban controls completed the WHOQOL-BREF questionnaire and Social Support Rating Scale (SSRS) by stratified sampling in 2011. Spearman’s correlation was performed to clarify the relationship between social support and HRQOL in migrants. Multiple linear regression analyses were used to identify the variables that were associated with HRQOL. Results: The general health, psychological health, and environmental scores of QOL in new-generation migrant workers were lower than in urban workers. New-generation migrants had poorer social support compared with urban controls with regard to general support, objective support, and support utilization. A positive correlation was found between social support and HRQOL. Workers with a higher level of education achieved better psychological, environmental, and general scores than workers with a primary education. Physical, social, environmental, and general health was also closely connected with the age factor. Physical health scores were higher in males than in females. Conclusion: These data suggest that new-generation migrant workers have significant impairment in HRQOL and receive less social support. HRQOL may be affected by social support, education, age, and gender.