Inclusion Criteria:
* Must be able to understand and willing to sign an informed consent document.
* Participants aged 18 years or older.
* Morphologically documented AML in patients with relapsed/refractory disease, defined as having \>= 20% blasts in bone marrow or peripheral blood.
* Documented TP53 mutation as seen on standard diagnostics in AML.
* Aspartate aminotransferase (AST) \< 3 × upper limit of normal (ULN).
* Alanine aminotransferase (ALT) \< 3 × ULN.
* Total bilirubin \< 1.5 × ULN (except for patients with known Gilbert's syndrome).
* Adequate renal function as defined by calculated creatinine clearance (according to the Cockcroft-Gault equation) \> 40 mL/min OR serum creatinine \< 1.5 × ULN.
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) =\< 2.
* Must be able to take oral medication.
* Individuals of childbearing potential (IOCBP) must agree to use highly-effective method(s) of contraception during the study and six months after the last dose of study drugs. IOCBP must have a negative pregnancy test prior to study enrollment.
* Sperm producing individuals must agree to use an adequate method of contraception starting with the first dose of study therapy through 3 months after the last dose of study drugs.
* Participants must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of their cancer.
Exclusion Criteria:
* Isolated myeloid sarcoma (patients must have blood or marrow involvement with AML to enter the study).
* Acute promyelocytic leukemia (M3).
* Active central nervous system (CNS) involvement by AML.
* Clinical signs/symptoms of leukostasis which has failed urgent therapy of at least 3 days duration, which may have included hydroxyurea or leukapheresis.
* Known active human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C infection.
* Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis.
* Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent or who have agent-related toxicity that has not resolved to grade 1 or less. If the half-life of an investigational agent is unknown, patients must wait 1 week after discontinuing it before receiving the first dose of study treatment. An investigational agent is one for which there is no approved indication by the United States (US) Food and Drug Administration (FDA).
* Prior entrectinib for other malignancies (prior decitabine therapy will not be excluded).
* Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up.
* Patients who are otherwise felt unable to comply with the protocol, in the opinion of the investigator.
* Any other significant medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient participating in the trial or would confound the interpretation of the results of the trial.
* Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic (New York Heart Association \[NYHA\] class III or IV) congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction at presentation of AML, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
* Patients with uncontrolled infection shall not be enrolled until infection is treated and controlled.
* Participants with prior documented history of malabsorption syndrome (e.g., short gut syndrome) that might limit the bioavailability of study medications will be excluded.
