Internet addiction (IA) is common among adolescents and significantly determined by sociocultural and economic factors. The aim of this study was to compare the prevalence of IA among adolescents between Macau and mainland China and also examine its association with quality of life. A total of 2892 secondary school students were included. Standardized instruments were used to measure IA, depressive symptoms and quality of life. The overall prevalence of IA was 23.7%, with 32.5% in Macau and 19.8% in mainland China. Students in Macau were more likely to suffer from IA than those in mainland China (OR = 2.15, p < 0.001). Correlates of IA included being in higher school grades, poor academic performance, and more severe depressive symptoms. Students with IA reported lower quality of life in physical, psychological, social, and environmental domains. IA is common among Chinese adolescents, particularly in Macau. Considering the negative impact of IA on health and quality of life, regular screening and effective interventions should be undertaken for young Internet users.