Inclusion Criteria:

* For Arms A, B, C, D, E patients must have relapsed or refractory acute leukemias or high-risk MDS for which no standard therapies are anticipated to result in a durable remission
* Age \>= 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use acceptable contraceptive methods (abstinence, intrauterine device \[IUD\], oral contraceptive or double barrier device, such as a condom, diaphragm, or cervical/vault cap), for 16 weeks after the last dose of study drug, and must have a negative serum or urine pregnancy test within 1 week prior to beginning treatment on this trial; nursing patients are excluded; sexually active men must also use acceptable contraceptive methods for the duration of time on study and for at least 16 weeks after the last dose of study drug; pregnant and nursing patients are excluded because the effects of ONC201on a fetus or nursing child are unknown
* Must be able and willing to give written informed consent
* The interval from prior treatment to time of study drug administration should be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents; if the patient is on hydroxyurea to control peripheral blood leukemic cell counts, the patient must be off hydroxyurea for at least 24 hours before initiation of treatment on this protocol; persistent clinically significant toxicities from prior therapy must not be greater than grade 1
* Serum creatinine \< 2.0 mg/dl
* Total bilirubin =\< 1.5 x the upper limit of normal (ULN) unless considered due to Gilbert's syndrome
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =\< 3 x the ULN unless considered due to organ leukemic involvement
* Relapse \> 6 months since autologous or allogeneic stem cell transplantation provided:

* No active graft-versus-host disease (GVHD \> grade 1)
* No treatment with high dose steroids for GVHD (up to \>= 20 mg prednisolone or equivalent per day)
* No treatment with immunosuppressive drugs with the exception of low dose cyclosporine and tacrolimus

Exclusion Criteria:

* Uncontrolled intercurrent illness including, but not limited to uncontrolled infection, symptomatic congestive heart failure (New York Heart Association class III and IV), uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Active heart disease including myocardial infarction within previous 3 months, symptomatic coronary artery disease, arrhythmias not controlled by medication, or uncontrolled congestive heart failure (New York Heart Association class III and IV)
* Patients receiving any other standard or investigational treatment for their hematologic malignancy within past 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents
* Subject has been diagnosed or treated for another malignancy within 3 years of enrolment, except in situ malignancy, or low-risk prostate, skin or cervix cancer after curative therapy
* Known history of seropositive for human immunodeficiency virus (HIV) antibodies (HIV1 and HIV2), hepatitis C antibody (Hep C Ab) or a hepatitis B carrier (positive for hepatitis B surface antigen \[HBsAg\])
* Active drug use or alcoholism
* Known or active central nervous system (CNS) involvement by leukemia
* Concomitant use of strong CYP3A inhibitors