Inclusion Criteria:  Adults 18 to 75 years with previously untreated de novo acute myeloid leukemia (AML), AML with myelodysplastic syndromes (MDS) features, or therapy-related AML.  Nucleophosmin-1 (NPM1)-mutated disease documented in a local or the Sponsor's central testing facility.  Note: Participants with concurrent FMS-like tyrosine kinase 3 (FLT3) mutation but without access to midostaurin (eg, either for lack of health authority approval or reimbursement) may also enroll; participants with a concurrent FLT3 mutation will not be allowed to receive a FLT3 inhibitor at any time during the study treatment period.  Note: Participants with local test results for nucleophosmin-1 mutated (NPM1-m) (and/or FLT3 mutational status) may enroll, provided appropriate samples are sent to the Sponsor's central testing facility for NPM1-m companion diagnostic development.  Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0, 1, or 2.  Adequate hepatic and renal function defined as:  Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times the upper limit of normal (ULN), except those with hepatic involvement by AML, as documented by either computed tomography (CT) or ultrasound, in whom levels of AST and ALT < 5 times ULN are acceptable; total bilirubin < 1.5 times ULN unless elevated due to Gilbert's Disease or hemolysis. Calculated creatinine clearance > 40 mL/min or serum creatinine < 1.5 times ULN. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) ≤ 1.5 x ULN unless receiving therapeutic anticoagulation. Left ventricular ejection fraction ≥ 45% confirmed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan.  Exclusion Criteria:  Isolated myeloid sarcoma (ie, participants must have peripheral blood and/or bone marrow involvement by AML) or acute promyelocytic leukemia. Known central nervous system (CNS) involvement with leukemia. Active infection with hepatitis B, C, or known human immunodeficiency virus (HIV).  Known active coronavirus disease 2019 (COVID-19) either symptomatic or asymptomatic, as determined by nasopharyngeal swab for severe acute respiratory syndrome (SARS) coronavirus 2 (SARS CoV-2) ribonucleic acid (RNA) or antigen.  Note: Participants with a history of SARS-CoV-2 nasopharyngeal carriage (either with or without symptoms), who have subsequently tested negative on follow-up nasopharyngeal swab and are without signs or symptoms of COVID-19 may enroll. Participants who are fully vaccinated against SARS-CoV-2 may enroll.  Disseminated intravascular coagulation with active bleeding or signs of thrombosis. History of prior allogeneic hematopoietic stem cell transplant or solid organ transplant.  Treatment with proton pump inhibitors (PPIs) from 7 days prior to enrollment until 48 hours after completion of entospletinib (ENTO) or placebo.  Note: PPIs are likely to interfere with ENTO absorption, thus requiring a 7-day washout period. Histamine (H2) receptor antagonists and antacids are allowed for use during the study treatment period.  Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia.  Note: Participants may not receive AML-directed therapy prior to enrollment other than hydroxyurea or leukapheresis for acute management of hyperleukocytosis.  Clinical signs/symptoms of leukostasis that have failed therapy including hydroxyurea and/or leukapheresis of at least 3 days duration.  Clinically significant heart disease defined as:  New York Heart Association Class 3 or 4 congestive heart failure, Acute myocardial infarction ≤ 6 months before enrollment, Symptomatic cardiac ischemia/unstable angina ≤ 3 months before enrollment, History of clinically significant arrhythmias (eg, ventricular tachycardia or fibrillation; Torsades de Pointe) including Mobitz type II 2nd degree or 3rd degree heart block without a permanent pacemaker in place. Participants with a corrected congenital long measure between Q wave and T wave in the electrocardiogram (QT) interval (using the Fredericia formula, Fridericia correction of the QT measure [QTcF]) > 480 msec or Long QT Syndrome. Evidence of ongoing, uncontrolled systemic bacterial, fungal, or viral infection at the time of study treatment initiation, including but not limited to persistent fever or positive cultures in the setting of appropriate antimicrobial therapy. Unable to swallow tablets or concurrent disease affecting gastrointestinal function such as, malabsorption syndrome, gastric or small bowel resection, bariatric surgery, inflammatory bowel disease, or bowel obstruction.