• For the lead in phase: Patients \>= 18 years of age with a diagnosis of relapsed and/or refractory AML will be eligible. Patients who have had prior treatment with venetoclax will be allowed to participate in the lead in phase and cohort A

• For the dose expansion cohort A (relapsed/refractory \[R/R\] AML): Patients \>= 18 years of age with a diagnosis of relapsed and/or refractory AML will be eligible

• For the dose expansion cohort B (de novo AML): Patients \>= 18 years to 69 years of age; patients in this cohort must have received no prior therapy for AML

• Prior therapy with hydroxyurea, hematopoietic growth factors, or tretinoin (ATRA) (for emergency use for stabilization) is allowed with no washout. A cumulative dose of ara-C of up to 3 g for emergency stabilization in patients with rapidly proliferating disease is also allowed provided it was administered \> 48 hrs prior to enrollment

• Bilirubin =\< 2 mg/dL

• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =\< 3 x upper limit of normal (ULN) or \< 5 x ULN if related to leukemic involvement

• Creatinine =\< 1.5 x ULN

• Known cardiac ejection fraction of \> or = 45% within the past 3 months

• Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2

• A negative urine or serum pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial. A woman of childbearing potential is defined as a woman who has not been naturally postmenopausal for at least 12 consecutive months, or who had no previous surgical sterilization

• Patient must have the ability to understand the requirements of the study and signed informed consent. A signed informed consent by the patient or his legally authorized representative is required prior to their enrollment on the protocol