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Adult onset hemophagocytic lymphohistiocytosis (HLH) is a rare condition, usually secondary to either a precipitating infective or hematologic malignancy. We present a case of Epstein–Barr virus associated HLH in a 55-year-old female receiving treatment for a glioblastoma (GBM). It is possible that HLH is under recognized, as patients with GBM often have features of a nonspecific systemic inflammatory response syndrome, multiorgan failure and cognitive decline. A high index of suspicion and increased awareness can help improve timeliness of diagnosis. Therapeutically, Epstein–Barr virus associated HLH in patients with solid organ malignancy poses significant challenges. An individualized, multidisciplinary approach is essential when managing adult-onset HLH and providers will need to be mindful of the high mortality rate despite treatment.