Inclusion Criteria:

* Patients must have relapsed/refractory primary (ie, de novo) or secondary (progression of myelodysplastic syndrome \[MDS\] or myeloproliferative neoplasms \[MPN\], or therapy-related) acute myeloid leukemia (AML) according to the World Health Organization (WHO) classification with \>= 5% leukemic blasts in the bone marrow
* Patients may have received prior therapies and there are no limits on number of therapies

* Note: There is a requirement of 7 day washout from prior therapy or 5 half-lives, whichever is shorter
* Patient must have documentation of an IDH1 R132 mutation obtained prior to registration. IDH mutational status will be assessed locally
* Patients must understand and voluntarily sign an informed consent form (ICF) prior to any study-related assessments/procedures being conducted
* Patient is willing and able to adhere to the study visit schedule and other protocol requirements
* Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
* Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x upper limit of normal (ULN), unless considered due to leukemic organ involvement (within 28 days prior to registration)
* Serum total bilirubin \< 1.5 x ULN (within 28 days prior to registration)

* Higher levels are acceptable if these can be attributed to ineffective erythropoiesis, =\< 3 times the upper limit of normal for Gilbert's syndrome (eg, a gene mutation in UGT1A1), or leukemic organ involvement
* Serum creatinine or creatinine clearance \< 2 x ULN or \>= 30 mL/min based on the Modification of Diet in Renal Disease (MDRD) glomerular filtration rate (GFR) (within 28 days prior to registration)
* Patients must agree to serial bone marrow aspirate/biopsies
* Females of childbearing potential (FOCBP) may participate, providing they meet the following conditions: Agree to practice true abstinence from sexual intercourse or to use two highly effective contraceptive methods, of which one must be a barrier method (eg, combined \[containing estrogen and progestogen\] or progestogen only associated with inhibition of ovulation, oral, injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or male partner sterilization \[note that a vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the FOCBP trial participant and that a vasectomized partner has received medical assessment of the surgical success\]) at screening and throughout the study, and for at least 4 months following the last study treatment.

* NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

* Has not undergone a hysterectomy or bilateral oophorectomy
* Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months)
* Female patients must have a negative serum beta-subunit of human chorionic gonadotropin (beta-hCG) pregnancy test (sensitivity of at least 25 mIU/mL) 28 days prior to registration on study and have a negative serum or urine (investigator's discretion under local regulations) β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the start of study treatment in the Treatment Period.

* Note: the screening serum pregnancy test can be used as the test prior to the start of study treatment in the Treatment Period if it is performed within the 72-hour time frame)
* Male patients must agree to practice true abstinence from sexual intercourse or agree to the use of highly effective contraceptive methods (as described above) with non-pregnant female partners of child bearing potential at screening and throughout the course of the study and should avoid conception with their partners during the course of the study and for at least 4 months following the last study treatment.

* Furthermore, the male subject must agree to use a condom while treated with ivosidenib and for at least 4 months following the last ivosidenib dose

Exclusion Criteria:

* Patients who are suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype are not eligible
* Patients who have had prior therapy with ivosidenib are not eligible.

* Note: prior treatment with other IDH inhibitors are allowed
* Patients who have immediate life-threatening, uncontrolled medical problem that would prevent treatment on a clinical trial per investigator's discretion are not eligible
* Patients who have significant active cardiac disease within 28 days prior to study registration, including New York Heart Association (NYHA) class III or IV congestive heart failure; acute coronary syndrome (ACS); and/or stroke; or left ventricular ejection fraction (LVEF) \< 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 28 days prior to study registration are not eligible
* Patients who have prior history of malignancy, other than MDS, MPN, or AML are not eligible unless the subject has been free of the disease for \>= 1 year prior to the start of study treatment. However, subjects with the following history/concurrent conditions are allowed:

* Basal or squamous cell carcinoma of the skin
* Carcinoma in situ of the cervix
* Carcinoma in situ of the breast Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis clinical staging system)
* Patients who are known to have short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally are not eligible
* Patients who are taking the following sensitive CYP substrate medications that have a narrow therapeutic range are excluded from the study unless the subject can be transferred to other medications at least 5 half-lives or 14 days whichever is shorter prior to the start of study treatment: phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, tizanidine (CYP1A2), CYP2C8, CYP3A4/5, and CYP2B6
* Patients who are known to be taking strong CYP3A4 inducers or sensitive CYP3A4 substrate medications that have a narrow therapeutic window are not eligible, unless they can be transferred to other medications within \>= 5 half-lives prior to dosing or unless the medications can be properly monitored during the study
* Patients with an active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment) are not eligible
* Patients who have known or suspected hypersensitivity to any of the components of study therapy are not eligible
* Patient who has corrected QT (QTc) interval (Frederica's correction \[QTcF\]) \>= 480 ms) at screening unless attributable to bundle branch block or pacemaker are not eligible. If prolonged QTc is attributed to medications the patient must be transferred to other medications and QTc corrected to selection parameters prior to enrollment
* Female patients who are pregnant or nursing are not eligible
* Patients who have any significant medical condition, laboratory abnormality, or psychiatric illness that the treating physician believes would prevent the subject from participating in the study are not eligible