<p>Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the emergence of autoantibodies and deposition of immune complexes. SLE presents with heterogeneous multi-organ involvement that varies among patients and its mechanisms have been investigated to facilitate appropriate stratification and treatment selection. Bulk RNA-seq and bulk ATAC-seq have provided important insights into the pathogenesis of SLE; however, these approaches are inherently limited by their reliance on predefined cell subsets and known markers, which can introduce bias and restrict their ability to fully resolve cellular heterogeneity. Recent advances in multi-omics analyses have enabled the investigation of multi-layered information beyond single-cell RNA sequencing (scRNA-seq) alone and have contributed substantially to elucidating the pathogenesis of SLE. Although the emergence of autoreactive B cells and the production of autoantibodies in SLE are well established, the mechanisms of evasion from negative selection remain unclear. Multi-omics analyses have revealed key aspects of SLE pathogenesis, particularly the expansion of atypical B cells (ABCs), an autoreactive population driven by extrafollicular pathways. Furthermore, beyond transcriptional profiling, multi-omics analysis has emerged as an additional investigative method, which combines scRNA-seq with other modalities. Spatial analyses, for instance, have provided critical insights into the tissue localization and persistence of autoreactive B cells within inflammatory niches in lupus nephritis, suggesting that local microenvironments contribute to treatment resistance. Additionally, B cell receptor (BCR) sequencing has revealed distinctive BCR features in SLE, such as reduced somatic hypermutation, increased repertoire naiveness, and increased immunoglobulin variable region heavy chain gene (IGHV4-34) usage in B cells in bone marrow and affected organs (not only in peripheral blood). Furthermore, emerging multimodal approaches integrating spatial, transcriptomic, and epigenomic information further highlight pathogenic cell–cell interactions and inflammatory circuits that cannot be captured by scRNA-seq alone. In this review, we summarize recent multi-omics studies that elucidate the origin, differentiation, and tissue localization of pathogenic B cells in SLE. We provide an overview of the multi-omics analyses focusing on B cells so far, especially at single-cell resolution, and discuss their possible applications in precision medicine.</p>