Purpose: The impact of physical fitness (PF) on adolescents’ health-related quality of life (HRQOL) is an important health issue in China. The purpose of this study was to identify whether body mass index (BMI), cardiorespiratory fitness (CRF), and musculoskeletal fitness (MSF) influences HRQOL among Chinese adolescents. Method: The participants were 10,007 students (boys = 5276, 14.14 years ± 1.79; girls = 4829, 14.22 years ± 1.81) who were randomly selected from 30 secondary schools in Shandong, China. BMI, CRF, MSF, and HRQOL were measured and analyzed using ANCOVA and multiple regression. Results: BMI and physical fitness variables were partially associated with HRQOL in Chinese adolescents. ANCOVA showed a significant difference among BMI categories in terms of physical sense (PS), living convenience, and self-satisfaction (SS) for boys, but this difference was only seen with social activity opportunity (SAO) for girls. Multiple regression found that BMI was significantly associated with SAO. For boys, CRF was associated with the teacher and student relationship and SS, whereas MSF was only associated with PS. For girls, CRF was significantly linked with the parent and children relationship, learning capacity, and attitudes and self-perception (S-P), while MSF was associated with S-P. Conclusion: Enforcing physical activity and enhancing PF will be a crucial pathway in improving adolescents’ HRQOL in China.