To demonstrate potent efficacy, a cancer vaccine needs to activate both innate and adaptive immune cells. Personalized cancer vaccine strategies often require the identification of patient‐specific neoantigens; however, the clonal and mutational heterogeneity of cancer cells presents inherent challenges. Here, extracellular nanovesicles derived from alpha‐galactosylceramide‐conjugated autologous acute myeloid leukemia (AML) cells (ECNV‐αGC) are presented as a personalized therapeutic vaccine that activates both innate and adaptive immune responses, bypassing the need to identify patient‐specific neoantigens. ECNV‐αGC vaccination directly engages with and activates both invariant natural killer T (iNKT) cells and leukemia‐specific CD8+ T cells in mice with AML, thereby promoting long‐term anti‐leukemic immune memory. ECNV‐αGC sufficiently serves as an antigen‐presenting platform that can directly activate antigen‐specific CD8+ T cells even in the absence of dendritic cells, thereby demonstrating a multifaceted cellular mechanism of immune activation. Moreover, ECNV‐αGC vaccination results in a significantly lower AML burden and higher percentage of leukemia‐free survivors among cytarabine‐treated hosts with AML. Human AML‐derived ECNV‐αGCs activate iNKT cells in both healthy individuals and patients with AML regardless of responsiveness to conventional therapies. Together, autologous AML‐derived ECNV‐αGCs may be a promising personalized therapeutic vaccine that efficiently establishes AML‐specific long‐term immunity without requiring the identification of neoantigens. An autologous extracellular nanovesicle vaccine derived from alpha‐galactosylceramide‐conjugated acute myeloid leukemia (AML) cells directly activates both innate immune cells and AML‐specific CD8+ T cells without having to define tumor antigens. It induces strong antitumor immune memory and synergizes with chemotherapy to prevent relapse in hosts with AML. Thus, it can be developed as a platform for personalized vaccines in humans.