The World Health Organization (WHO) recommends that schools adopt a whole-school strategy for healthy behaviors involving different health professionals. The present systematic review aimed to evaluate the efficacy of nurse-led interventions in collaboration with kinesiologists on physical activity and lifestyle behaviors’ outcomes in school settings. The protocol was registered in PROSPERO (ID: CRD42022343410). The primary research study was developed through the PICOS question: children and adolescence 6–18 years (P); school nurse-led interventions in promoting physical activity (PA) and reducing sedentary behaviors (I); usual lessons, no intervention focusing on PA (C); PA levels, sedentary behaviors, and healthy lifestyle behaviors (O); experimental or observational study with original primary data and full-text studies written in English (S). Seven studies were included. Interventions were heterogeneous: besides physical activities carried out in all studies, the interventions were based on different health models and strategies (counselling, face-to-face motivation, education). Five out of seven articles investigated PA levels or their related behaviors using questionnaires, and two used ActiGraph accelerometers. Lifestyle behaviors were assessed with heterogeneous methods. Five out of seven articles showed an improvement in at least one outcome after the interventions, whereas two papers showed a statistically non-significant improvement. In conclusion, school interventions involving nurses, also in association with other professionals such as kinesiologists, can be effective in reducing sedentary behaviors and improving healthy lifestyles in children and adolescents.