A growing body of research suggests that neuropsychiatric disorders are closely associated with a background state of chronic, low-grade inflammation. This insight highlights that these disorders are not just localized to dysfunction within the brain, but also have a systemic aspect, which accounts for the frequent comorbid presentation of chronic inflammatory conditions and metabolic syndromes. It is possible that a treatment resistant subgroup of neuropsychiatric patients may benefit from treatment regimens that target their associated proinflammatory state. Lifestyle factors such as physical activity (PA) and exercise (i.e. structured PA) are known to influence mental health. In turn, mental disorders may limit health-seeking behaviors - a proposed "bidirectional relationship" that perpetuates psychopathology. PA is renowned for its positive physical, physiological and mental health benefits. Evidence now points to inflammatory pathways as a potential mechanism for PA in improving mental illness. Relevant pathways include modulation of immune-neuroendocrine and neurotransmitter systems, the production of tissue-derived immunological factors that alter the inflammatory milieu and neurotrophins that are critical mediators of neuroplasticity. In this paper, we will focus on the role of PA in positively improving mental health through potential modulation of chronic inflammation, which is often found in individuals with mental disorders. In a related paper by Edirappuli and colleagues (2020), we will focus on the role of nutrition (another significant lifestyle factor) on mental health. Thus, inflammation appears to be a central process underlying mental illness, which may be mitigated by lifestyle modifications. Lifestyle factors are advantageous as first-line interventions due to their cost efficacy, low side-effect profile, and both preventative and therapeutic attributes. By promoting these lifestyle modifications and addressing their limitations and barriers to their adoption, it is hoped that their preventative and remedial benefits may galvanize therapeutic progress for neuropsychiatric disorders.