Posterior reversible encephalopathy syndrome (PRES) is a rare and potentially harmful complication in patients receiving targeted chemotherapy. We herein present a case of PRES that occurred after 33 days of high-dose bortezomib treatment and propose both overwhelmed cerebral autoregulation and toxin-mediated blood-brain barrier damage as the underlying mechanisms based on the imaging findings. A favorable recovery was observed two days after achieving stringent hypertension control and withholding bortezomib. Follow-up images obtained two weeks later unveiled a dramatic remission, with faint areas of subcortical hyperintensity in the bilateral parieto-occipital regions. With explicit clinical and imaging features, this case highlights the need for early recognition of PRES during the clinical course of bortezomib therapy.