The purpose of this systematic review was to determine how combinations of physical activity (PA), sedentary behaviour (SB), and sleep were associated with important health indicators in children and youth aged 5–17 years. Online databases (MEDLINE, EMBASE, SPORTdiscus, CINAHL, and PsycINFO) were searched for relevant studies examining the relationship between time spent engaging in different combinations of PA, SB, and sleep with the following health indicators: adiposity, cardiometabolic biomarkers, physical fitness, emotional regulation/psychological distress, behavioural conduct/pro-social behaviour, cognition, quality of life/well-being, injuries, bone density, motor skill development, and self-esteem. PA had to be objectively measured, while sleep and SB could be objectively or subjectively measured. The quality of research evidence and risk of bias for each health indicator and for each individual study was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. A total of 13 cross-sectional studies and a single prospective cohort study reporting data from 36 560 individual participants met the inclusion criteria. Children and youth with a combination of high PA/high sleep/low SB had more desirable measures of adiposity and cardiometabolic health compared with those with a combination of low PA/low sleep/high SB. Health benefits were also observed for those with a combination of high PA/high sleep (cardiometabolic health and adiposity) or high PA/low SB (cardiometabolic health, adiposity and fitness), compared with low PA/low sleep or low PA/high SB. Of the 3 movement behaviours, PA (especially moderate- to vigorous-intensity PA) was most consistently associated with desirable health indicators. Given the lack of randomized trials, the overall quality of the available evidence was low.