Circular RNAs (circRNAs), characterized by their unique covalently closed circular structure, are highly stable, conserved, and expressed in a tissue-, cell-, and developmental stage-specific manner. A lot of evidence has indicated that circRNAs play a crucial role in diversified biological and pathological processes by sponging microRNAs (miRNAs), interacting with proteins, or being translated into particular proteins, etc. Recent advancements in bioinformatics have revealed a close association between circRNAs and the development of neuropsychiatric diseases, including major depressive disorder (MDD). Increasingly, researchers emphasize the significant impact of abnormal circRNA expression and its targets on the pathogenesis of MDD. However, the detailed mechanisms involved remain elusive. Research has articulated the important role of neuronal cell dysfunction in MDD. Glia cells are the most abundant cell type in the central nervous system (CNS) and provide critical roles in MDD via intercellular-interaction-dependent pathogenic mechanisms. In this review, we extensively explore the newly identified roles of circRNAs in MDD. We summarize their novel mechanisms from cellular and molecular perspectives by deciphering how circRNAs interplay between neurons and neurogliocytes, followed by how circRNAs are tailored to synaptic plasticity and stress pathways under a variety of circumstances. Last, we discuss and predict their potential clinical values of diagnosis and therapy.© 2025. The Author(s), under exclusive licence to Springer Nature Limited.