Older adults with acute myeloid leukemia (AML) who are not fit for standard chemotherapy historically have poor outcomes. Approximately 12–15% of older patients with AML harbor isocitrate dehydrogenase 2 (IDH2) gene mutations. Enasidenib is an oral inhibitor of mutant IDH2 proteins. Among 39 patients with newly diagnosed mutant-IDH2 AML who received enasidenib monotherapy in this phase I/II trial, median age was 77 years (range 58–87) and 23 patients (59%) had had an antecedent hematologic disorder. The median number of enasidenib treatment cycles was 6.0 (range 1–35). The most common treatment-related adverse events were indirect hyperbilirubinemia (31%), nausea (23%), and fatigue, decreased appetite, and rash (18% each). Treatment-related grade 3–4 cytopenias were reported for eight patients (21%); there was no treatment-related grade 3–4 infections. Twelve patients achieved a response (overall response rate 30.8% [95% CI 17.0%, 47.6%]), including seven patients (18%) who attained complete remission. At a median follow-up of 8.4 months, the median duration of any response was not reached (NR). Median overall survival for all patients was 11.3 months (95% CI 5.7, 15.1), and was NR for responders. Oral, outpatient targeted treatment with enasidenib may benefit older adults with newly diagnosed mutant-IDH2 AML who are not candidates for cytotoxic regimens.