Rituximab, a chimeric anti-CD20 monoclonal antibody, is widely used to treat autoimmune diseases and hematologic malignancies through B-cell depletion, yet paradoxical autoimmune phenomena, including drug-induced lupus erythematosus, have been increasingly recognized. While paradoxical autoimmune phenomena following rituximab therapy have been reported, drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) represents an exceedingly rare complication. This case reports rituximab-induced SCLE in a patient with Sjögren’s disease and demonstrates the dual therapeutic efficacy of anifrolumab in managing both drug-induced cutaneous lupus and interferon-driven systemic manifestations. A 69-year-old woman with established primary Sjögren’s disease and cryoglobulinemic vasculitis developed biopsy-proven subacute cutaneous lupus erythematosus with clinical onset approximately 4 months following rituximab administration, with histopathological confirmation at Month 9. The patient presented with characteristic erythematous lesions on the trunk and back, which subsequently recurred with extension to the face and décolleté; histopathological examination revealed interface dermatitis and a positive lupus band test on direct immunofluorescence. Treatment with anifrolumab (300 mg intravenously every 4 weeks) resulted in complete resolution of rituximab-induced SCLE. Subsequent addition of low-dose mycophenolate mofetil (1,000 mg daily) achieved complete remission of cryoglobulinemic vasculitis, with sustained disease control maintained on this anifrolumab-based regimen. Clinicians should maintain vigilance for paradoxical cutaneous reactions following B-cell-depleting therapies, particularly in patients with underlying Sjögren’s disease and anti-Ro/SSA positivity.