Background: Patients with del17p or TP53^mut acute myeloid leukemia (AML) have short durations of remission and dismal overall survival. The benefit of fludarabine-based intensive chemotherapy (IC), such as FLAG-IDA or FLAG, remains unclear. Additionally, while venetoclax has revolutionized the treatment of AML, the comparative efficacy of venetoclax with a hypomethylating agent (HMA; decitabine or azacitidine) remains unknown in patients with del17p or TP53^mut AML. We aimed to compare FLAG-based regimens to venetoclax + HMA in this subgroup of disease while controlling for IC candidacy. Methods: We retrospectively analyzed 79 patients with AML and TP53^mut or del17p. Of these, 25 met study inclusion criteria: age 70 or younger, treated with front-line IC, and treated with either fludarabine-based therapy (with or without idarubicin, N = 15) or venetoclax + HMA (N = 10) in the subsequent line. To further reduce confounding effects, no patients in the FLAG group received venetoclax + HMA, and no patients in the venetoclax group received FLAG. We recorded baseline patient and disease characteristics, cytogenetic risk, 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 Mantel-Cox test. Results: We analyzed 25 patients with TP53^mut or del17p AML initially treated with IC and subsequently underwent salvage therapy with FLAG or venetoclax + HMA. The salvage regimen in each cohort was initiated after a median of one line of therapy, with no difference between groups (p = 0.089). Patients in the FLAG cohort were significantly younger than the venetoclax cohort (54 y. vs 62 y., p = 0.046), but there were no significant differences in the Charlson Comorbidity Index scores (4 vs 4, p = 0.127) or ECOG scores (1 vs 2, p = 0.053) at salvage. There were also no differences in the median TP53 variant allele frequency (VAF) between the cohorts (p = 0.095). The composite complete remission (CRR: CR + CRi) rate was 28.6% in the venetoclax cohort, compared to 46.7% in the FLAG cohort (p = 0.648). Patients that received FLAG had significantly prolonged median overall survival compared to venetoclax + HMA (13.1 m. vs 4.5 m., p = 0.004). Conclusions: In patients with del17p or TP53^mut AML, FLAG-based salvage appears to offer a significant improvement in overall survival following IC failure. Prospective trial designs are needed to confirm these findings.