Interleukin-10 (IL-10) production by B cells plays a critical role in regulating inflammatory responses, yet the mechanisms controlling its expression remain poorly understood. We identified a conserved noncoding sequence (CNS-9) as an essential regulatory element for IL-10 expression in mouse B cells. Comprehensive genomic analyses revealed that CNS-9 functions as an enhancer bound by the transcription factor NFATc1, which facilitates chromatin looping between CNS-9 and the IL-10 promoter to dr