Inclusion Criteria:  • COHORT 1A AND 1B: New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 1B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; World Health Organization (WHO) grade III and IV H3 wildtype gliomas.  COHORT 2A AND 2B: Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In cohort 2B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas. COHORT 2A AND 2B: Participants must be within 4-14 weeks of completion of radiation. COHORT 3A AND 3B: Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In cohort 3B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas. COHORT 3A AND 3B: Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation. Age 2 to 39 years Participants must have recovered from all acute side effects of prior therapy Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 kg)  From the projected start of scheduled study treatment, the following time periods must have elapsed: At least 7 days after last dose of a biologic agent or beyond time during which adverse events are known to occur for a biologic agent, 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.  For participants who have received radiotherapy, participants in cohort 2 must be between 4 and 14 weeks from the completion of local up-front radiotherapy. The use of bevacizumab to control radiation therapy-induced edema is allowed. Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m2 /dose continuously during radiation therapy for 42 days) or dexamethasone is allowed. Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 3 days prior to baseline magnetic resonance imaging (MRI) scan. Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (1.0g/l) AND Platelet count >= 100,000/mm^3 (100x10^9/l) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 OR A serum creatinine within the normal limits for age Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age AND Serum glutamate pyruvate transaminase (SGPT)(alanine aminotransferase (ALT)) =< 2 x ULN AND Serum albumin >= 2 g/dL Serum lipase =< ULN at baseline No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of > 92% while breathing room air. Diarrhea < grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 Non-fasting glucose < 125 mg/dL without the use of antihyperglycemic agents If non-fasting glucose > 125 mg/dL, a fasting glucose should be done. If fasting glucose =< 160 mg/dL without the use of antihyperglycemic agents, participants will meet adequate metabolic function criteria No history of congestive heart failure or family history of long QT syndrome. Participants who are at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs must have adequate cardiac function. QTC < 470 msec. Shortening fraction of >= 27% by echocardiogram (echocardiogram (ECHO) to be done only if history of abnormal cardiac function or abnormal electrocardiogram [EKG] at baseline. Abnormal EKGs should be discussed with the study chairs). Participants with seizure disorder may be enrolled if seizure disorder is well controlled The effects of the study drugs on the developing human fetus are unknown. For this reason, females of child-bearing potential and males must agree to use adequate contraception. Adequate methods include: hormonal or barrier method of birth control; or abstinence prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation. Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants =< 16 years of age. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. Subjects must be willing to provide archival formalin-fixed embedded (FFPE) and frozen tissue specimens for biomarker studies, if available. A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.  Exclusion Criteria:  COHORT 1A AND 1B: Prior exposure to radiation therapy. COHORT 1A AND 2A: Deemed not appropriate for tissue resection/biopsy. COHORT 3A AND 3B: Prior exposure to re-irradiation for tumor progression. Diagnosis of a histone H3 wildtype grade II diffuse astrocytoma Participants who are currently receiving another investigational drug. Investigational imaging agents or agents used to enhance tumor visibility on imaging or during tumor biopsy/resection should be discussed with the study chairs. Participants who are currently receiving other anti-cancer agents Participants with a known disorder that affects their immune system, such as human immunodeficiency virus (HIV) or hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy. Note: Participants that are currently using inhaled, intranasal, ocular, topical or other non-oral or non-intravenous (IV) steroids are not necessarily excluded from the study but need to be discussed with the study chair. Participants with uncontrolled infection  Participants with history of congestive heart failure are at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs must have adequate cardiac function. Electrocardiogram (ECG) must be obtained as and verify the following. If an abnormal reading is obtained, the ECG must be repeated in triplicate.  QTC < 470 msec; Shortening fraction of >= 27% by echocardiogram Female participants of childbearing potential must not be pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy (as clinically indicated). Active illicit drug use or diagnosis of alcoholism History of allergic reactions attributed to compounds of similar chemical or biologic composition as the agents used in study Evidence of disseminated disease, including diffuse leptomeningeal disease or evidence of CSF dissemination Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration. Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs (EIAEDs), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent corticosteroids is allowed.