Post-transplant lymphoproliferative disorder (PTLD) confined to the brain and spinal cord is a rare and aggressive neoplasm that often occurs immediately post-transplant. Long-term survival remains generally poor due to graft failure or chemotoxicity. We present a case of a 53-year-old female who presented with new-onset left-sided weakness ten weeks after kidney transplantation. The patient experienced progressive left arm weakness and numbness, accompanied by dizziness and headache. She was given anti-thymocyte globulin as induction therapy then maintained on tacrolimus (6 mg per day), mycophenolate mofetil (2000 mg per day), and prednisone (15 mg per day). There was no personal or family history of malignancy. Creatinine and urinalysis were unremarkable. Infectious workups were negative, including the serum Epstein-Barr virus IgM assay. Tacrolimus trough levels were within the therapeutic range of 8-10 ng/mL. Cranial MRI/MRA revealed a right fronto-parietal lesion (2.6 x 2 x 2.3 cm) and a right inferior frontal lobe lesion (3.3 x 1.5 x 1.7 cm) with perimetric edema and mild mass effects. PET-CT scan was negative for metastatic lesions. Cranial excision biopsy showed hypercellular tissue with atypical round cells and necrosis, with immunohistochemical stains consistent with high-grade diffuse large B-cell lymphoma. The patient was treated with 12 cycles of high-dose methotrexate (5000 mg/m²), followed by leucovorin. Tacrolimus trough levels were maintained in a lower range of 4–5 ng/mL, with a stable eGFR of 80–90 mL/min/1.73 m². There was complete recovery of the left-sided weakness and numbness, with interval resolution of the right fronto-parietal and inferior frontal mass and the perilesional edema on repeat cranial MRI. Early detection, prompt diagnosis, and aggressive treatment with high-dose methotrexate and tumor excision led to improved patient outcomes. With the rise of innovative immunosuppressants, screening for malignancy in at risk patients cannot be overemphasized.