• Ability to provide informed consent

• Ability to tolerate intensive therapy with vosaroxin 90 mg/m\^2 and cytarabine

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 at time of study entry

• Morphologically confirmed new diagnosis of AML in accordance with World Health Organization (WHO) diagnostic criteria

• Patients who have received hydroxyurea alone or have previously received non-cytotoxic therapies for myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) (e.g., thalidomide or lenalidomide, 5-azacytidine or decitabine, histone deacetylase inhibitors, low-dose Cytoxan, tyrosine kinase or dual tyrosine kinase \[TK\]/SRC proto-oncogene, non-receptor tyrosine kinase \[src\] inhibitors) will be allowed

• Serum creatinine =\< 2.0 mg/dL

• Hepatic enzymes (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\]) =\< 2.5 x upper limit of normal

• Total bilirubin =\< 1.5 x upper limit of normal unless clearly related to Gilbert's disease, hemolysis or leukemic infiltrate

• FOR PATIENTS IN STAGE 1 (PATIENTS #1-#17)

• \>= 55 years of age with AML of any risk classification, or 18-54 years of age with high-risk AML disease based on one of the following:

‣ Antecedent hematologic disorder including myelodysplasia (MDS)-related AML (MDS/AML) and prior myeloproliferative disorder (MPD)

⁃ Treatment-related myeloid neoplasms (t-AML/t-MDS)

⁃ AML with FMS-like tyrosine kinase 3 (FLT3) - internal tandem duplication (ITD)

⁃ Myeloid sarcoma

⁃ AML with multilineage dysplasia (AML-MLD)

⁃ Adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 21q or 17p; t(6;9); t(9;22); trisomy 8; trisomy 13; trisomy 21; complex karyotypes (\>= 3 clonal abnormalities); monosomal karyotypes

• FOR PATIENTS IN STAGE 2 (ENROLLED PATIENT #18 AND BEYOND)

• \>= 55 years of age with AML of any risk classification, or 18-54 years of age with intermediate or high risk AML as defined by National Comprehensive Cancer Network (NCCN) risk assignment