DNA hypomethylating agents (HMAs) are widely used to treat acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), but most treated patients relapse and lack standard treatment options. Using high-throughput screening, the approved all-trans retinoic acid (ATRA) is identified that exhibit high selectivity in killing HMA-resistant AML cells compared to parental cells. Mechanistically, HMA-resistant cells are overloaded with DNA hypomethylation-associated endogenous viral double-stranded RNA (dsRNA) which, however, fails to trigger an anticancer interferon (IFN) immune response due to downregulation of dsRNA sensor retinoic acid-inducible gene I (RIG-I). ATRA compensates for RIG-I expression, thereby re-triggering IFN response and potently inhibiting HMA-resistant AML cell lines, xenograft mice, and patient-derived primary cells. A library of potential RIG-I-inducing compounds is rationally constructed and screened, in which the approved M3 AML treatment drug tamibarotene (TAM) exhibits strikingly 28036-fold selectivity and 779 pm IC50 in killing HMA-resistant AML cells. ATRA and TAM do not selectively inhibit p53-mutant cancer cells. Together, this study uncovers a common resistance mechanism in HMA-treated AML patients and, in addition, provides highly potent and selective agents that can overcome resistance through re-triggering IFN anticancer immune response.