Navitoclax, Venetoclax, and Decitabine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Previously Treated With Venetoclax

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative
* For participants under the age of 18 years, documentation of adolescent assent by the participant and consent of both parents or guardian
* Adults aged \>= 18 years
* Adolescent patients aged \>= 16 years and \< 18 years weighing at least 45 kg who have no other standard-of-care option for treatment
* Eastern Cooperative Oncology Group (ECOG) =\< 2
* Patients with histologically confirmed AML, according to World Health Organization (WHO) criteria, with refractory/relapsed (R/R) disease following a venetoclax-containing regimen who are ineligible for therapies known to be effective for treatment of their AML.

  * Patients with extramedullary disease may be included if they also have marrow involvement
  * Patients with acute promyelocytic leukemia (APL) will not be eligible
* Fully recovered from the acute toxic effects (except alopecia) to =\< grade 1 of prior anti-cancer therapy
* Ability to swallow pills
* Absolute neutrophil count (ANC) \>= 750/mm\^3 (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)

  * NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement
* White blood cell (WBC) =\< 25 x 10\^9/L prior to initiation of study therapy. Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may be required (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
* Platelets \>= 75,000/mm\^3

  * NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
* Total bilirubin =\< 1.5 X upper limit of normal (ULN) (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
* Aspartate aminotransferase (AST) =\< 3.0 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
* Alanine aminotransferase (ALT) =\< 3.0 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
* Creatinine clearance of \>= 45 ml/min per 24-hour urine test or the Cockcroft-Gault formula (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
* If in the absence of anticoagulants: International normalized ratio (INR) OR prothrombin (PT) =\< 1.5 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
* If in the absence of anticoagulants: Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
* Left ventricular ejection fraction (LVEF) \>= 50%

  * Note: To be performed within 28 days prior to day 1 of protocol therapy
* Corrected QT interval (QTc) =\< 480 ms

  * Note: To be performed within 28 days prior to day 1 of protocol therapy
* Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (RPR) (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)

  * If positive, Hepatitis C RNA quantitation must be performed
* Meets other institutional and federal requirements for infectious disease titer requirements

  * Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy
* Women of child-bearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)
* Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months (males) and 6 months (females) after the last dose of protocol therapy

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

Exclusion Criteria:

* Hematopoietic stem cell transplant within 100 days prior to day 1 of protocol therapy
* Chemotherapy, radiation therapy, biological therapy, or immunotherapy within 14 days or 5 half-lives, whichever is shorter, prior to day 1 of protocol therapy with the following exceptions:

  * Subjects will be allowed to have been on venetoclax at screening and remain on it through treatment start.
  * Hydroxyurea is allowed prior to treatment and through cycle 1 for control of rapidly progressing leukemia
* Strong or moderate CYP3A4 inducers within 14 days prior to day 1 of protocol therapy
* Grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit consumed within 3 days prior to the first dose of study drug
* Immunosuppressants (steroids =\< 10 mg/day of oral prednisone or equivalent is allowed) within the last 28 days
* Hematopoietic growth factors in the last 14 days
* Must not have received or planning to receive live vaccine while being on study or 4 weeks before and after completion of treatment
* Herbal medications known to affect platelet function within 14 days of therapy initiation
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
* Active graft-versus-host-disease (GVHD)
* Active central nervous system (CNS) disease
* No measurable disease in the bone marrow
* Active diarrhea
* Gastrointestinal disorder that interferes with oral drug absorption such as malabsorption syndrome
* Clinically significant cardiac morbidities (class III/IV cardiovascular disability according to the New York Heart Association classification, arrhythmia not stable on medical management, acute cardiovascular ischemic event within 6 months of enrollment, etc.)
* Clinically significant uncontrolled illness
* Active infection requiring antibiotics
* Active/uncontrolled HIV infection, acquired immunodeficiency syndrome (AIDS), or currently taking contraindicated medications for HIV control
* Diagnosis of Gilbert's disease
* Any other active malignancy at time of enrollment. Exceptions include basal/squamous cell carcinoma, in situ adequately treated breast and uterine cancer
* Females only: Pregnant or breastfeeding
* Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)