•Longer-term physical activity improves mental health and cognition in youth.•Improvements coincide with altered fMRI and EEG parameters in frontal brain areas.•Physical activity is related to BDNF increases; associations with cortisol are more complex.•Physical activity interventions shall target lower fit and vulnerable youth. To investigate putative neurobiological mechanisms that link longer-term physical activity interventions to mental health and cognitive outcomes using randomised controlled trials in children, adolescents and young adults. A range of medical and psychological science electronic databases were searched (MEDLINE, EMBASE, Scopus, Web of Science, PsychINFO). Original research studies were selected, data were extracted and quality was appraised. Sixteen primary papers were included, ranging from healthy and community samples to subclinical and clinical populations across a variety of age ranges and using different neurobiological measures (e.g. magnetic resonance imaging, electroencephalography, cortisol, brain-derived neurotropic factor). The majority of studies report improvement in mental health and cognition outcomes following longer-term physical activity interventions which coincide with neurobiological alterations, especially neuroimaging alterations in activation and electrophysiological parameters in frontal areas. Future research should include measures of pre-existing fitness and target those who would benefit the most from this type of intervention (e.g. those with a lower level of fitness and at risk for or with mental health problems).