Glioblastoma (GBM) is an incurable primary brain tumor with a poor prognosis. Resection, radiation therapy, and temozolomide (TMZ) are insufficient to increase survival, making the treatment limited. Thus, the search for more effective and specific treatments is essential, making plants a promising source for elucidating new anti-glioblastoma compounds. Accordingly, this study investigated the effects of four fractions of hexane and ethyl acetate extract of Annona coriacea Mart., enriched with acetogenins, against GBM cell lines. All four fractions were selectively cytotoxic to GBM cells when compared to TMZ. Moreover, A. coriacea fractions delayed cell migration; reduced cytoplasmic projections, the metalloproteinase 2 (MMP-2) activity; and induced morphological changes characteristic of necroptosis, possibly correlated with the increase in receptor-interacting protein kinase 1 and 3 (RIP-1 and RIP-3), apoptosis-inducing factor (AIF), and the non-activation of cleaved caspase 8. The present findings reinforce that fractions of A. coriacea Mart. should be considered for more studies focusing treatment of GBM.