Systemic lupus erythematosus (SLE) is characterized by a large number of anti-autoantibodies produced by abnormally activated B cells, which form immune complexes with autoantigens to induce systemic inflammation, leading to the involvement of multiple systems and organs. Existing treatment strategies targeting B cells (such as belimumab, telitacicept, and rituximab) had limited efficacy. Recently, CD19 targeting chimeric antigen receptor (CAR)-T cell has shown excellent efficacy in the treatment of SLE. However, autologous CAR-T cell therapy has potential risks such as cytokine release syndrome (CRS), T cell tumors, and infections, and it is expensive. CAR-natural killer (NK) cell therapy, on the other hand, is an off-the-shelf cellular therapy with high safety, no neurotoxicity or tumorigenic risk, and with low treatment costs. Currently, CAR-NK cell has achieved remarkable research results in treating hematological malignancies, and preliminary clinical studies of CAR-NK cell therapy for SLE have showed good efficacy, excellent safety, and predictable durability. This article focuses on the characteristics of the new generation of universal CAR-NK cell and the latest clinical research results for the treatment of relapsed and refractory SLE, offering insights into its promising future in the treatment of SLE and B-cell-related autoimmune diseases.