Epigenetic memory refers to self-sustaining transcriptional states that persist through cell division even after the initiating signal is removed. This property enables cells to stabilise or resist gene expression changes in response to perturbations such as cancer therapies. However, how anti-cancer drugs influence epigenetic memory and whether these effects can be therapeutically exploited remains poorly understood. Using acute myeloid leukaemia (AML) as a model, we show that the Menin-MLL1 inhibitor, Revumenib, induces durable transcriptional rewiring and stable silencing at a subset of target genes following long-term drug withdrawal (up to 63 days). Temporal chromatin profiling revealed the selective deposition of PRC2-mediated H3K27me3 at the loci which exhibit long-term repression, whereas reactivated genes gradually reacquired activating marks over several weeks. Single cell RNA sequencing further showed that drug withdrawal triggered increased transcriptional heterogeneity, suggesting the destabilisation of cell identity. We also find that therapies directly targeting chromatin regulators, including EZH2 (Tazemetostat) and DNMT1 (GSK-3685032), can similarly induce epigenetic memory in leukaemia as well as breast and lung cancer cell lines through direct disruption of H3K27me3 or DNA methylation, respectively. In contrast, inhibition of signalling (FLT3i, Gilteritnib) or transcription (BETi) produced only transient transcriptional effects, indicating that lasting memory following a perturbation requires direct and specific modification of chromatin state. To test whether drug-induced memory can be exploited therapeutically, we performed comparative CRISPR screens, which uncovered distinct dependencies in iMenin-induced epigenetically reprogrammed versus naïve cells, revealing emergent vulnerabilities. Incorporating epigenetic agents (iMenin and DNMT1i) into sequential regimens markedly sensitised AML cells to targeted therapies such as Venetoclax or Gilteritnib. Notably, sequential Menin-Venetoclax treatment was as effective as simultaneous combination therapy. Together, these findings establish drug-induced epigenetic memory as a selective and durable mechanism that provides a conceptual framework for the design of rational and effective sequential cancer therapies for clinical implementation.