Glioblastoma multiforme (GBM) is a deadly human cancer. It occurs in the brain cells or in spinal cord. GBM stem cells are reported to be resistant to treatment and reappearance is unpreventable. GBM stem cells are the target of Zika virus (ZIKV) which is known to cause impaired brain development leading to microcephaly in human embryos. The virus ensures the survival of mice having gliomas. ZIKV has been reported as an oncolytic virus targeting GBM cells selectively. Here, we will discuss the immunological aspect of protection against GBM mediated by ZIKV. When ZIKV was introduced into the brain, the recruitment of CD8+ T and myeloid cells to the tumor microenvironment was augmented. CD8+ T cells were needed for ZIKV-mediated tumor clearance. Here we will also discuss the role of cellular gasdermin D (GSDMD) in efficient killing of a human GBM cell line that was promoted by ZIKV infection. The ZIKV protease cleaves specifically human GSDMD for activating caspase-independent pyroptosis thus damaging, both the naive neighboring as well as viral protease-harboring cells.