A 37-year-old male was admitted with an atypical presentation of central nervous system (CNS) aspergillosis while on ibrutinib therapy for a CNS relapse of mantle cell lymphoma. This case highlights the importance of a high clinical suspicion of opportunistic infections in patients receiving small-molecule kinase inhibitors. This report includes a review of reported cases of Aspergillus infections in patients receiving ibrutinib and the shared features of these cases.