Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, increasingly affecting pediatric and adult populations. Neuropsychiatric manifestations (i.e., cognitive dysfunction and mood disorders) appear to occur with greater severity and poorer prognosis in childhood vs adult‐onset SLE, negatively impacting school function, self‐management, and psychosocial health, as well as lifelong health‐related quality of life. In this review, we describe pathogenic mechanisms active in childhood‐onset SLE (cSLE) such as maladaptive inflammatory processes and ischemia, which are hypothesized to underpin central phenotypes in cSLE cases, while the role of alterations in protective central nervous system (CNS) barriers (i.e., the blood‐brain barrier) are also discussed. Recent findings derived from novel neuroimaging approaches are highlighted as the methods employed in these studies hold potential for identifying CNS abnormalities that would otherwise remain undetected with conventional MRI studies (e.g., T2‐weighted/ FLAIR sequences). Furthermore, we propose that a more robust presentation of neuropsychiatric symptoms in childhood‐onset SLE (cSLE) is in part due to the harmful impact of a chronic inflammatory insult on a developing central nervous system (CNS). Although the immature status of the CNS may leave cSLE patients more vulnerable to harboring neuropsychiatric manifestations, the same property may represent greater urgency to reverse the maladaptive effects associated with a pro‐neuroinflammatory state, provided that effective diagnostic tools and treatment strategies are available. Finally, considering the crosstalk between the CNS and other organ systems affected in cSLE, we postulate that a finer understanding of this interconnectivity and its role in the clinical presentation in cSLE is warranted.image