Background: Maintaining a healthy lifestyle is crucial for safeguarding the well-being and quality of life perception, appropriate growth, and development of children and adolescents, while also mitigating the risk of future adult-onset diseases. Objective: To assess associations between perceived quality of life and healthy lifestyle and related outcomes in Spanish children and adolescents. Methods: Cross-sectional analysis of 8–16-year-old children and adolescents (n = 3534) were included in the nationwide study of Physical Activity, Sedentarism, and Obesity in Spanish Youth (PASOS). Data were collected through (1) questionnaires on health-related quality of life (HRQoL), healthy lifestyle outcomes (dietary intake, physical fitness, sleep, and screen time), and (2) anthropometric measurements for weight status assessment. Data were analysed by logistic regression, using the health-related quality of life (HRQoL) as the grouping variable. Results: Participants with a lower HRQoL were those with a lower adherence to the MedDiet and lower achievement of the recommended daily intake of fruit and vegetables. They were also less likely to follow the recommendations for screen time and sleep (with the exception of the weekend) compared to participants with a higher HRQoL. Participants with a lower HRQoL showed a lower healthy weight status and poorer physical fitness than those with a higher HRQoL. Conclusions: Healthy eating habits, healthy weight status (normal weight), appropriate sleep time, physical fitness, and limited screen time play a crucial role in the perceived quality of life in children and adolescents.