Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2.
* IDH1-R132 mutated disease status as assessed by local laboratory. 2HG-producing IDH1 variants outside of R132 (i.e. R100) may be eligible after discussion with the principal investigator (PI).
* Relapsed/refractory AML, or treatment-naive patients with AML who are not eligible for standard induction chemotherapy. Patients with high-risk myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) (defined as \>= 10% bone marrow blasts, or intermediate or high risk by International Prostate Symptom Score \[IPSS\], Revised \[R\]-IPSS or Dynamic \[D\]-IPSS) may also be eligible after discussion with the PI
* Direct bilirubin =\< 2 x upper limit of normal (ULN) unless deemed to be related to underlying leukemia.
* Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =\< 3 x ULN unless deemed to be related to underlying leukemia.
* Creatinine clearance \>= 30 ml/min based on the Cockcroft-Gault equation.
* Willing and able to provide informed consent.
* In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy) agents.
* Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug.

Exclusion Criteria:

* Patients with known allergy or hypersensitivity to ivosidenib or venetoclax.
* Patients who have previously received either ivosidenib or venetoclax.
* Patients with any concurrent uncontrolled clinically significant medical condition including infection, laboratory abnormality, or psychiatric illness, which could place the patient at unacceptable risk of study treatment
* The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled central nervous system (CNS) leukemia. (2) use of hydroxyurea and/or one dose of cytarabine (up to 2 g/m\^2) for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy.
* Patients receiving concomitant treatment with strong CYP3A4 inhibitors within 3 days of start of study therapy (including posaconazole and voriconazole).
* Patients receiving concomitant strong CYP3A inducers (avasimibe, carbamazepine, phenytoin, rifampin, rifabutin, St. John's wort) within 3 days of start of study therapy.
* Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI).
* Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
* Patients with a concurrent active malignancy under treatment.
* Corrected QT (QTc) interval using Fridericia's formula (QTcF) \>= 450 msec. Bundle branch block and prolonged QTc interval are permitted after discussion with the PI.
* Known active hepatitis B (HBV) or hepatitis C (HCV) infection or known human immunodeficiency virus (HIV) infection.
* Subject has a white blood cell count \> 25 x 10\^9/L. (Note: Hydroxyurea is permitted to meet this criterion.)
* Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception.

* Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide).