Background: FLT3 mutations in AML are associated with high relapse rates and shorter survival compared to FLT3 wild-type. After intensive chemotherapy (IC) failure, clinicians can choose between several salvage regimens; however, the optimal therapy sequence remains unclear. This study compares two salvage therapies: gilteritinib or venetoclax and a hypomethylating agent (HMA; decitabine or azacitidine). Methods: We retrospectively analyzed 129 patients with AML and mutated FLT3-ITD or FLT3-TKD. We identified those that failed first-line IC (CPX-351 or conventional 7+3 with or without midostaurin) and received salvage. We compared patients treated with gilteritinib or venetoclax + HMA as the next line of therapy from January 1, 2018 to January 1, 2022 at VCU Massey Cancer Center. To reduce confounding, no patient in the venetoclax group received gilteritinib in a subsequent line of therapy. We recorded baseline disease characteristics, genetic risk by ELN 2022, induction regimens, response, and survival. We used Fisher’s exact test for nominal data and Mann-Whitney for ordinal data. We analyzed survival by the Kaplan-Meier method and compared groups with the log-rank test. Results: We identified 129 patients with FLT3-ITD or FLT3-TKD mutated AML and analyzed them over 228 treatment phases. In the front-line setting, 89 (68.9%) patients received IC; 55 (61.8%) received salvage therapy for relapsed or refractory disease, and 16 received either gilteritnib (N=6) or venetoclax-based (N=10) salvage. The median age of the gilteritinib cohort was significantly younger (p = 0.007), but there were no differences between groups with respect to ELN 2022 adverse risk (p = 0.633) or between ECOG (p = 0.700) or Charlson Comorbidity Index scores (p = 0.104). The composite complete remission (CCR; CR + CRi) rate of the gilteritinib cohort was 20.0%, compared to 60.0% for the venetoclax cohort (p = 0.282). No patient in the gilteritinib cohort achieved MRD negativity. Among responders in the venetoclax cohort, MRD negativity was 75.0% (p = 0.400). The median overall survival in the gilteritinib cohort was 3.9 months — significantly shorter than 7.8 months for the venetoclax cohort (p = 0.048). Conclusions: Venetoclax + HMA appears superior to gilteritinib for subsequent therapy after IC failure in FLT3^mut AML, despite the gilteritinib cohort being significantly younger. The limitations of this study include its retrospective nature — prospective trials are needed to confirm these findings.