A 55-year-old woman with stage IV follicular lymphoma developed progressive multifocal leukoencephalopathy (PML) during rituximab maintenance therapy following bendamustine-rituximab induction. Although pembrolizumab administration was initiated for suspected PML, her neurological status deteriorated, ultimately leading to death. This case highlights the limited therapeutic response to pembrolizumab in profoundly immunocompromised patients, highlighting the need for timely diagnosis, immunovirological assessment, and individualized innovative management approaches for PML.