Dynamic interactions between genetic predispositions and environmental exposures significantly shape the escalating prevalence of childhood obesity. This systematic review synthesizes observational and clinical trial evidence on the gene-environment interplays influencing childhood obesity, highlighting the role of genetic variants and environmental moderators such as dietary habits, physical activity, sleep durations, parental behaviors, socioeconomic status, ethnicity, gender, as well as lifestyle interventions. We conducted an exhaustive search across 5 databases (Medline, PubMed, EMBASE, Web of Science, and Cochrane Library), adhering to PRISMA guidelines. We ultimately included 147 studies that investigated these interplays in diverse populations. Specifically, 83 studies focused on gene-diet interplays, 23 on gene-physical activity, 5 on sedentary behavior, 3 on screen time, 7 on sleep duration, 10 on parental behavior, 4 on socioeconomic status, 16 on gender, 8 on age, 7 on ethnicity, and 13 on the effects of lifestyle interventions. Notably, we meta-analyzed energy expenditure and macronutrient consumption, including carbohydrates, proteins, and fats, as well as the proportion of energy supplied by each nutrient between carriers and noncarriers of the FTO effect allele, revealing that carriers consumed a higher proportion of fat calories, with no other significant differences noted. This review demonstrates that genetic risk variants, particularly in FTO (e.g., rs9939609) and MC4R (e.g., rs17782313), amplify the adverse effects of obesogenic behaviors, offering insights into the intricate pathophysiology of childhood obesity and suggesting the potential for personalized interventions based on genetic profiles.Copyright © 2025 Elsevier Inc. All rights reserved.