Naive CD8+ T cell activation results in an autonomous program of cellular proliferation and differentiation. However, the mechanisms that underpin this process are unclear. Here, we profile genome-wide changes in chromatin accessibility, gene transcription, and the deposition of a key chromatin modification (H3K27me3) early after naive CD8+ T cell activation. Rapid upregulation of the histone demethylase KDM6B prior to the first cell division is required for initiating H3K27me3 removal at genes essential for subsequent T cell differentiation and proliferation. Inhibition of KDM6B-dependent H3K27me3 demethylation limits the magnitude of an effective primary virus-specific CD8+ T cell response and the formation of memory CD8+ T cell populations. Accordingly, we define the early spatiotemporal events underpinning early lineage-specific chromatin reprogramming that are necessary for autonomous CD8+ T cell proliferation and differentiation. Display omitted •Naive CD8+ T cell activation results in chromatin changes prior to first cell division•The H3K27me3 demethylase KDM6B is rapidly upregulated upon T cell activation•H3K27me3 demethylation occurs in a stepwise manner ensuring optimal T cell activation•Perturbation of KDM6B function results in suboptimal virus-specific CD8+ T cell memory Li et al. demonstrate that naive CD8+ T cell activation results in extensive KDM6B-dependent chromatin demethylation prior to first cell division. Inhibition of early chromatin demethylation resulted in dysregulated T cell activation and suboptimal virus-specific CD8+ effector and memory T cell responses.