Inclusion Criteria:
* Written informed consent/assent from the participant (or their legally authorized representative, parent(s), or legal guardian) must be obtained before any study-related procedures are conducted and participants must be willing to comply with all study procedures for the duration of the study.
* Aged 1 to \<18 years and weighing at least 7 kilograms (kg) at the time of providing informed consent/assent.
* Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, hemoglobin E (HbE)/β-thalassemia, or α-thalassemia/hemoglobin H (HbH) disease) based on Hemoglobin (Hb) electrophoresis, Hb high-performance liquid chromatography, and/or DNA analysis from the participant's medical record. If this information is not available from the participant's medical record, the test(s) can be performed by a local laboratory during the Screening Period. If a local laboratory is unable to perform the test(s), results from the comprehensive α- and β-globin genotyping performed by the study central laboratory can be used.
* Transfusion dependent, defined as 6 to 20 transfusion episodes (also referred to as "transfusion events") and a ≤6-week transfusion-free period during the 24-week period before randomization.
* If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization.
* Female participants who have attained menarche must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of informed consent/assent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can include an acceptable barrier method.
Exclusion Criteria:
* Pregnant or breastfeeding.
* Documented history of homozygous or heterozygous hemoglobin S (HbS) or hemoglobin C (HbC).
* Prior exposure to gene therapy or prior bone marrow or stem cell transplantation, including any prior exposure to myeloablative chemotherapy.
* Any conditions other than thalassemia expected to affect sexual maturation.
* Currently receiving treatment with luspatercept; the last dose must have been administered ≥36 weeks before randomization.
* Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 weeks before randomization.
* History of malignancy (active or treated) ≤5 years before providing informed consent/assent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ.
* History of active and/or uncontrolled cardiac or pulmonary disease or clinically relevant QT prolongation within 6 months before providing informed consent/assent.
* Hepatobiliary disorders, including but not limited to:
* Liver disease with histopathological evidence or clinical diagnosis of cirrhosis or severe fibrosis.
* Clinically symptomatic cholelithiasis or cholecystitis (prior cholecystectomy is not exclusionary).
* History of drug-induced cholestatic hepatitis.
* Aspartate Aminotransferase (AST) \>2.5\*Upper Limit of Normal (ULN) (unless due to hemolysis and hepatic iron deposition) and Alanine Transaminase (ALT) \>2.5\*ULN (unless due to hepatic iron deposition).
* Renal dysfunction as defined by an estimated glomerular filtration rate \<60 milliliters per minute (mL/min)/1.73-meter square (m\^2).
* Nonfasting triglycerides \>215 milligrams per deciliter (mg/dL) \[5 millimole per liter (mmol/L)\].
* Active infection requiring systemic antimicrobial therapy at the time of providing informed consent/assent. If antimicrobial therapy is required during the Screening Period, screening procedures should not be performed while antimicrobial therapy is being administered, and the last dose of antimicrobial therapy must be administered ≥7 days before randomization.
* Participants with known active hepatitis B or hepatitis C virus infection.
* Participants with known human immunodeficiency virus (HIV) infection.
* History of major surgery (including splenectomy) ≤ 6 months before providing informed consent/assent and/or a major surgical procedure planned during the study.
* Current enrollment or past participation (within ≤12 weeks or a timeframe equivalent to 5 half-lives of the investigational study drug before administration of the first dose of study drug, whichever is longer) in any other clinical study involving an investigational treatment or device.
* Receiving strong Cytochrome3A4/5 (CYP3A4/5) inhibitors that have not been stopped for ≥5 days or a timeframe equivalent to 5 half-lives (whichever is longer), or strong CYP3A4/5 inducers that have not been stopped for ≥4 weeks or a timeframe equivalent to 5 half-lives (whichever is longer), before randomization.
* Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed; the testosterone dose and preparation must be stable for ≥12 weeks before randomization.
* Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, magnesium stearate, and the Opadry filmcoat \[hypromellose, titanium dioxide, lactose monohydrate triacetin, and FD\&C Blue #2\]).
* Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data. Also excluded are:
* Participants who are institutionalized by regulatory or court order.
* Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).
