Glioblastoma (GBM) is a particularly aggressive brain cancer associated with high recurrence and poor prognosis. The standard of care, surgical resection followed by concomitant radio- and chemotherapy, leads to low survival rates. The local delivery of active agents within the tumor resection cavity has emerged as an attractive means to initiate oncological treatment immediately post-surgery. This complementary approach bypasses the blood–brain barrier, increases the local concentration at the tumor site while reducing or avoiding systemic side effects. This review will provide a global overview on the local treatment for GBM with an emphasis on the lessons learned from past clinical trials. The main parameters to be considered to rationally design fit-of-purpose biomaterials and develop drug delivery systems for local administration in the GBM resection cavity to prevent the tumor recurrence will be described. The intracavitary local treatment of GBM should i) use materials that facilitate translation to the clinic; ii) be characterized by easy GMP effective scaling up and easy-handling application by the neurosurgeons; iii) be adaptable to fill the tumor-resected niche, mold to the resection cavity or adhere to the exposed brain parenchyma; iv) be biocompatible and possess mechanical properties compatible with the brain; v) deliver a therapeutic dose of rationally-designed or repurposed drug compound(s) into the GBM infiltrative margin. Proof of concept with high translational potential will be provided. Finally, future perspectives to facilitate the clinical translation of the local perisurgical treatment of GBM will be discussed.