Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that commonly manifests as cutaneous rashes, renal disease, gastrointestinal dysfunction, and cytopenia. Hematological anomalies are frequently associated with drug-induced toxicity in SLE patients. Colony-stimulating factors have been used to treat drug-induced cytopenia in past case reports; however, evidence suggests that colony-stimulating factors can exacerbate autoimmune disorders, including SLE. This case report presents two patients with SLE exacerbations after colony-stimulating factor administration. The first case is a young male with SLE who developed pancytopenia with a white blood cell count (WBC) of 1 × 10 cells/L. The patient was administered filgrastim during his initial admission and presented to the hospital 2 days after discharge in cardiac arrest with a WBC of 66.7 × 10 cells/L. The second case is a 49-year-old female with SLE who was administered sargramostim in response to a WBC count of 9 × 10 cells/L. The patient experienced a drastic increase in WBC followed by a cardiac arrest. These cases highlight the need for more research regarding the safe use of colony-stimulating factors in SLE patients.