Inclusion Criteria:

• * Be identified as high risk for recurrent colorectal adenomas, as defined by:
• * A diagnosis of FAP AND/OR
• * Findings of either \> 5 small (less than 1 cm) adenomas OR \>= 3 with at least one \>= 10 mm on most recent endoscopy performed in the past 5 years
• * Be \>= 18 years of age on day of signing informed consent
• * Have an Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
• * Leukocytes \>= 3,000/microliter
• * Absolute neutrophil count \>= 1,000/microliter
• * Platelets \>= 100,000/microliter
• * Total bilirubin within normal institutional limits
• * Aspartate aminotransferase (AST) (serum (glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (\[SGPT\]) =\< 1.5 x institutional upper limit of normal
• * Creatinine =\< 1.5 x institutional upper limit of normal
• * Participant is due to undergo a standard of care lower gastrointestinal (GI) colonoscopy for detection and removal of colorectal polyps. On this colonoscopy, participant is required to have:
• * Two (2) adenomatous polyps (pathologic confirmation of adenoma in non-FAP participants is required prior to starting therapy) of at least five (5) mm in size
• * At least one (1) polyp within reach of a flexible sigmoidoscope (which will be retained in the colon or rectum and marked)
• * In addition to polypectomy, six (6) biopsies of normal colonic mucosa \>= 1 cm from a collected polyp will also be collected
• * Willing to undergo a second, research intent endoscopic procedure (either sigmoidoscopy or colonoscopy), approximately 12 weeks after initiating ONC201 treatment
• * Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
• * Life expectancy of at least 5-years
• * ONC201 is an imipridone agent with the potential for teratogenic or abortifacient effects. For this reason and because imipridones potential teratogenic effects are unknown, men and women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for four weeks after study treatment is completed. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should STOP the study medication and inform her study physician immediately
• * Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• * Prior history of hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome
• * Participants may not be currently receiving any other investigational agents or have received any investigational agents within the past four weeks
• * Prior history of invasive colorectal cancer
• * Prior invasive active neoplasm that is progressing or requires active treatment within 3 years from registration. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Participants with a history of prior invasive neoplasm diagnosed and treated greater than 3 years form registration may be considered with consultation of the primary investigator
• * Prior history of exposure to cytotoxic chemotherapy or ONC201
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201
• * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• * Pregnant and women who are nursing are excluded from this study because ONC201 is an imipridone agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with ONC201, breastfeeding should be discontinued if the mother is treated with ONC201