Invasive fungal disease (IFD) remains a challenging complication and a leading cause of death in the treatment of childhood acute leukemia (AL). Blinatumomab is a novel bispecific antibody targeting CD19, with excellent anti-tumor effects against B cell malignancies, including B cell acute lymphoblastic leukemia (B-ALL). Compared with standard chemotherapy, blinatumomab causes less immunosuppression. This report describes two children with B-ALL who experienced recurrent high fever during induction chemotherapy. Next-generation sequencing (NGS) detected Aspergillus in bronchoalveolar lavage fluid, skin tissue, blood, and cerebrospinal fluid. After antifungal therapy, the patients received 9 courses of blinatumomab combined with reduced-dose chemotherapy. Symptoms, signs, and imaging findings improved significantly, B-ALL remained in continuous remission in both patients, and no cytokine release syndrome, neurotoxicity, or fungal infection recurrence occurred. These cases suggest that alternating blinatumomab with reduced-dose chemotherapy is both effective and safe for patients with B-ALL suffering life-threatening infections in the setting of ALL therapy.