Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by immune dysregulation and autoantibody production. Despite advances in treatment, achieving sustained disease control remains challenging. Rituximab (RTX) and belimumab (BELI) are two B-cell-targeting biologics with complementary mechanisms of action, leading to increasing interest in their combination as a therapeutic strategy for refractory SLE. RTX depletes CD20+ B cells, whereas BELI inhibits B-lymphocyte stimulator (BLyS), reducing the survival of autoreactive B cells. Sequential therapy with these agents may mitigate B-cell repopulation and improve disease control. Recent studies, including SynBioSe and BEAT-LUPUS, suggest that RTX-BELI therapy can reduce autoantibody levels, neutrophil extracellular trap formation, and disease activity, with many patients achieving a lupus low disease activity state (LLDAS). However, the BLISS-BELIEVE and CALIBRATE trials did not demonstrate superiority over monotherapy, highlighting the need to refine patient selection. Combination therapy may be particularly beneficial in lupus nephritis, where BELI delays autoreactive B-cell reconstitution following RTX, potentially prolonging remission. While RTX-BELI therapy is generally well-tolerated, some studies report increased infections, necessitating careful patient monitoring. Lessons from other immune-mediated diseases, including inflammatory bowel disease and rheumatoid arthritis, underscore the potential benefits and risks of dual biologic therapy. Further research, including the ongoing SynBioSe-2 trial, is needed to clarify the optimal use, sequencing, and safety profile of RTX-BELI in SLE. Identifying biomarkers predictive of response may enable personalized treatment approaches, ultimately improving long-term outcomes for patients with refractory SLE.