The purpose of this research is to test the safety and effectiveness of the investigational drug ruxolitinib when it is combined with standard of care treatment (radiation therapy and temozolomide) for the treatment of newly diagnosed glioblastoma. Half the people in the study will be assigned to take the study drug ruxolitinib in addition to the standard of care temozolomide and radiation therapy and the other half will be assigned to the standard of care temozolomide and radiation therapy only. This assignment will be randomized in a 1-to-1 ratio, like the flip of a coin.

Inclusion Criteria:

1. Provision of signed informed consent form.

2. Stated willingness to comply with all study procedures and availability for the duration of the study.

3. Individuals of any sex, gender, race, or ethnicity ≥ 18 years of age.

4. Histologically confirmed glioblastoma as defined by the World Health Organization (WHO) 2021 Criteria (IDH-wildtype) that is either methylated, unmethylated, or indeterminate MGMT.

5. Confirmation that patient has sufficient tissue to undergo MGMT and IDH testing, as mandated.

6. Must have a Karnofsky performance status (KPS) ≥ 70% (i.e., the patient must be able to care for themself with occasional help from others).

7. Adequate organ (liver and renal) and bone marrow function within 14 days before randomization. For all parameters listed below, the most recent results available must be used:

   1. Absolute neutrophil count (ANC) ≥ 1500/mm3. Note: Granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 1 week prior to screening assessment.
   2. Platelet count ≥ 100,000/mm3. Note: Platelet transfusion is not allowed within 1 week prior to registration.
   3. Total bilirubin (TBL) ≤ 1.5 × institutional upper limit of normal (ULN).
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN.
   5. Serum albumin ≥ 2.5 g/dL.

8. Patients able to become pregnant: use of highly effective contraception for at least one (1) month prior to screening and agreement to use such a method. Should a participant become pregnant or suspect that they are pregnant while participating in this study, they should notify the treating physician immediately. Such individuals must have a negative pregnancy test.

9. Patients must have no concurrent malignancy except curatively treated early-stage bladder and prostate cancer that has been completed resected, basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast, adequately treated stage I or II cancer from which the patient is in complete remission. Patients with other prior malignancies must be disease-free for ≥ 3 years.

Exclusion Criteria:

1. Patients who are pregnant or breast-feeding. The anti-proliferative activity of this experimental drug and temozolomide may be harmful to the developing fetus or nursing infant.
2. Patients receiving concurrent therapy for their brain tumor (e.g., chemotherapeutics or investigational agents).
3. Patients with a concurrent or prior malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Patients who have been free of disease (any prior malignancy) for at least 3 years are eligible for this study.
4. Patients who have had repeat craniotomy for tumor therapy after receiving radiation therapy and temozolomide treatment.
5. Patients who received other chemotherapeutics or investigational agents in addition to their radiation therapy and concomitant temozolomide treatment.
6. Patient has previously taken ruxolitinib or is allergic to components of the study drug.
7. Patients using warfarin.
8. Uncontrolled immunodeficiency virus infection or active tuberculosis.
9. Patients with active serious infections requiring systemic therapy.
10. Known Active hepatitis B virus (HBV) or hepatitis C virus infection that requires treatment or at risk for HBV reactivation. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive. Participants with previous positive serology results must have negative polymerase chain reaction results.
11. Patient has significant abnormalities on screening electrocardiogram (EKG) and active and significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, New York Heart Association (NYHA) Grade ≥2 heart failure, uncontrolled hypertension, valvular disease, pericarditis, myocardial infarction, or other thrombosis events like including pulmonary embolism or deep vein thrombosis within 6 months of screening.
12. Any other serious medical/psychiatric condition, in the judgement of the investigator, that likely to interfere or limit compliance with study requirements/treatment.