Monosomy 7 and 7q deletions (-7/del(7q)) are the most common adverse cytogenetic event in acute myeloid leukemia (AML), linked to high relapse rates. We analyzed 115 AML patients with -7/del(7q) who achieved remission after induction therapy to characterize the mutational landscape from diagnosis to relapse. Median overall survival (OS) was 10.4 months, with improved survival in patients without TP53 mutation (13.04 vs. 8.6 months) or complex karyotype (12.4 vs. 8.6 months). TP53 mutations were most frequent (67% of cases at diagnosis) and persisted in 97% of patients at relapse. At time of relapse, patients with TP53 mutations had fewer co-occurring mutations in ASXL1, RUNX1, NRAS, PTPN11 and SRSF2 compared to TP53 wild-type patients. Patients with mutated TP53 and co-mutation in NF1, BCORL1, GATA2, or RUNX1 had shorter relapse-free survival (2 vs. 5 months) and OS (7.2 vs. 10.4 months) than those with TP53 mutation alone. Allogeneic transplant improved OS significantly, regardless of TP53 status.