Inclusion Criteria:
* 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.
Exclusion Criteria:
* Patients who are receiving any other investigational agents.
* Exception: COVID-19 vaccine and treatment is allowed
* Patient who have a prior or concurrent malignancy that may interfere with study treatment or safety.
* NOTE: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible. Per principal investigator (PI) discretion
* Patients who have a history of allergic reactions attributed to compounds of similar chemical composition to temozolomide or mycophenolate mofetil.
* Patients with spinal cord and diffuse leptomeningeal disease GBM
* Patients requiring live vaccinations within 2 weeks of initiation of MMF and/or TMZ therapy. Consider completion of vaccination with live vaccines prior to starting immunosuppressive therapy, as indicated.
* Patients on viral-vector based therapy due to increased risk for disseminated herpetic infection.
* Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible:
* Have uncontrolled epilepsy
* Have an uncontrolled intercurrent illness
* Concurrent malignancy (outside of glioblastoma) that requires tumor directed treatment
* Known deficiency of hypoxanthine-guanin-phosphoribosyltransferase (HGPRT) deficiency, e.g. Lesch-Nyhan- oder Kelley-Seegmiller-Syndrome.
* Known concurrent shingles, herpes, CMV (cytomegalovirus) infection
* Known concurrent opportunistic fungal infection
* Known concurrent or history of unexplained opportunistic infection
* Known immunodeficiency that could lead to opportunistic infections
* Psychiatric illness/social situations that would limit compliance with study requirements. Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints.
* Female patients who are pregnant or nursing. Pregnant women are excluded from this study because temozolomide is an alkylating agent with potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide, breastfeeding should be discontinued if the mother is treated with temozolomide.
* Patients who are unable to swallow oral medication or have problems/ diseases that affect absorption of oral medication.
* Patients with a known history of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV).
* Note: Temozolomide and mycophenolate mofetil are immunosuppressive agents. Patients with a known history of HIV, HBV, and HCV, and unexplained opportunistic infections are not eligible due to safety reasons
