• GROUPS 1-3: Histologically confirmed glioblastoma (GBM), IDH wild-type (by immunohistochemistry \[IHC\] R132H negative \[neg\] or sequencing). Astrocytoma with molecular features of GBM are eligible.

• GROUPS 1-3: Newly diagnosed glioblastoma and:

‣ Group 1: Received surgical resection or biopsy followed by chemoradiation;

⁃ Group 2: Received surgical resection or biopsy only and have documented unmethylated glioblastoma (may have been done at an outside facility);

⁃ Group 3: Received surgical resection or biopsy only

• GROUP S: Newly suspected glioblastoma or recurrent glioblastoma, and scheduled to undergo a standard of care surgical resection or biopsy.

• Stable or decreasing dose of corticosteroids equivalent to =\< 8 mg dexamethasone daily, for \>= 7 days prior to registration.

‣ Note: There are no restrictions on steroid use on study

• Patients must be age \>= 18 years.

• Patients must exhibit a Karnofsky performance status \>= 70.

• Leukocytes (white blood cells \[WBC\]) \>= 3,000/mcL (within 14 days prior to study registration)

• Absolute neutrophil count (ANC) \>= 1,500/mcL (within 14 days prior to study registration)

• Hemoglobin (Hgb) \>= 8 g/dL (within 14 days prior to study registration) (transfusion may be used for eligibility if \>= 7 days)

• Platelets (PLT) \>= 100,000/mcL (within 14 days prior to study registration) (transfusion or growth factor may be used for eligibility if \>= 7 days).

• Total bilirubin =\< 2x institutional upper limit of normal (ULN) (within 14 days prior to study registration)

• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\])/Alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional ULN (within 14 days prior to study registration)

• Creatinine =\< 1.5 x Institutional ULN (within 14 days prior to study registration)

• International normalized ratio (INR) =\< 1.5 x ULN (within 14 days prior to study registration)

• Prothrombin time (PT)/Partial thromboplastin Time (PTT) =\< 1.5 x ULN (within 14 days prior to study registration)

• Females of child-bearing potential (FOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from time of informed consent, for the duration of study participation, and for 3 months following completion of therapy. Should a female patient become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception from time of informed consent, for the duration of study participation, and 4 months after completion of administration.

‣ 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)

• FOCBP must have a negative pregnancy test within 14 days prior to registration on study.

• Patient or their legally authorized representative must provide written, signed, and dated informed consent prior to study registration. Patient or their legally authorized representative (LAR) must have the ability to understand and the willingness to sign a written informed consent document. The patient or their LAR must be willing and able to comply with the protocol for the duration of the study.

‣ NOTE: no study-specific screening procedures may be performed until written consent has been obtained.