Inclusion Criteria:
* Presumptive diagnosis of glioblastoma based on magnetic resonance imaging (MRI) imaging within 14 days prior to registration.
* NOTE: Patients who undergo treatment with Toca 511 whose final pathology shows diagnosis other than glioblastoma (e.g. anaplastic astrocytoma or oligodendroglioma or any other histology) will be treated with Toca FC and chemoradiation; however they will not be analyzed in the primary endpoint. The outcomes of these patients will be reported descriptively. Similarly the patients with anaplastic astrocytoma or oligodendroglioma or any other histology treated on the standard-of-care arm will be reported separately and they are allowed to receive the treatment per choice of the treating physician/ investigator (for e.g. radiation therapy \[RT\] plus temozolomide or RT plus procarbazine-lomustine-vincristine \[PCV\])
* In addition, patients who have undergone biopsy with diagnosis of glioblastoma and who have never received any chemotherapy and/or radiation and are candidates for \>= 80% resection of enhancing region are eligible
* The tumor must be unifocal, confined to the supratentorial compartment and based on the pre-operative evaluation, the patient is a candidate for \>= 80% resection of enhancing region
* Measurable disease preoperatively, defined as at least 1 contrast enhancing lesion, with 2 perpendicular measurements of at least 1 cm, as per Response Assessment in Neuro-Oncology (RANO) criteria
* The hematoxylin and eosin (H\&E) slide and formalin-fixed paraffin-embedded (FFPE) tumor tissue block must be available to be sent for mandatory central pathology review after registration
* Patients must be able to undergo an evaluation by MRI within 96 hours post surgery to assess extent of resection
* Karnofsky performance status \>= 70 within 14 days prior to registration
* History/physical examination within 14 days prior to registration
* Platelet count \>= 100,000/mm\^3 (within 14 days prior to registration)
* Hemoglobin (Hgb) \>= 10 g/dL (within 14 days prior to registration)
* Absolute neutrophil count (ANC) \>= 1,500/mm\^3 (within 14 days prior to registration)
* Absolute lymphocyte count (ALC) \>= 1000/mm\^3 (within 14 days prior to registration)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) (unless has Gilbert?s syndrome) (within 14 days prior to registration)
* Alanine aminotransferase (ALT) =\< 2.5 x ULN (within 14 days prior to registration)
* Estimated glomerular filtration rate of at least 50 mL/min by the Cockcroft Gault formula (within 14 days prior to registration)
* Women of childbearing potential (women who have not had \>=12 months of non therapy induced amenorrhea or are not surgically sterile) must have had a negative serum pregnancy test within 14 days prior to registration and must agree to use a birth control method in addition to barrier methods (condoms or diaphragm) during treatment with temozolomide
* If the patient is randomized to arm 2, the patient or patient?s partner must be willing to use barrier method of contraception for 12 months after receiving Toca 511 and 1 month after stopping Toca FC or until there is no evidence of the virus in the patient?s blood, whichever is longer
* The patient or a legally authorized representative must provide study-specific informed consent prior to registration
Exclusion Criteria:
* History of prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years
* A contrast enhancing brain tumor on MRI that is any of the following:
* Multi focal (defined as 2 separate areas of contrast enhancement measuring at least 10 mm in 2 planes that are not contiguous on either fluid attenuated inversion recovery \[FLAIR\] or T2 hyperintensity);
* Associated with either diffuse subependymal or leptomeningeal dissemination; or
* \> 50 mm in any dimension
* Active infection (excluding skin or toenail infections) requiring systemic antibiotic, antifungal or antiviral therapy within 28 days prior to registration
* Bleeding diathesis, or must take anticoagulants, or antiplatelet agents, including nonsteroidal anti inflammatory drugs (NSAIDs), at the time of the scheduled resection that cannot be stopped for surgery
* Known human immunodeficiency virus (HIV) positive status
* History of allergy or intolerance to flucytosine
* Swallowing difficulty that would prevent patient from being able to swallow either temozolomide or Toca FC or severe active mal-absorption
* Patients who are breast feeding or lactating
* Intent to undergo treatment with the Gliadel wafer at the time of this surgery or has received the Gliadel
* Prior to registration, steroid treatment beyond a maximum of 8 mg/day of dexamethasone (or equivalent) or a total of 8 weeks (56 days) is excluded
* Severe pulmonary, cardiac or other systemic disease, specifically:
* New York Heart Association \> =Class II congestive heart failure within 6 months (180 days) prior to registration, unless asymptomatic and well controlled with medication
* Uncontrolled or significant cardiovascular disease, clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes), clinically significant pulmonary disease (such as \>= grade 2 dyspnea)
* Any other disease that as per investigator assessment may affect the patient?s compliance or place the patient at higher risk of potential treatment complications
