This report describes a unique case of systemic diffuse large B-cell lymphoma (DLBCL) with initial ocular manifestations of bilateral optic disc edema and serous retinal detachment (SRD). A 29-year-old man presented with altered color vision in the left eye, mild fever, weakness, and headache, followed by bilaterally reduced visual acuity. Anterior segment and vitreous examinations showed no inflammation with sluggish response of light reflex. His fundus examination revealed bilateral multiple SRDs and optic disc swelling with choroidal thickening. On fluorescein angiography, pinpoint hyperfluorescence, associated dye pooling, and optic disc staining with leakage were found bilaterally. Laboratory studies revealed elevated C-reactive protein and mild leukocytosis with neutrophil predominance. He was provisionally diagnosed with probable Vogt-Koyanagi-Harada syndrome and received methylprednisolone pulse therapy. Five days later, his systemic condition deteriorated following initial ocular symptom improvement. Whole-body computerized tomography revealed clustered lymphadenopathies, which were interpreted as DLBCL after lymph node biopsy. His ocular condition improved after DLBCL chemotherapy. We hope to promote early recognition with appropriate workups through this case and literature review.