High-grade gliomas are the most frequently occurring brain tumors and carry unfavorable prognosis. Literature is controversial regarding the effects of surgery on cognitive functions. We analyzed a homogenous population of 30 patients with high-grade glioma who underwent complete resection. Patients underwent extensive neuropsychological analysis before surgery, 7 days after surgery, and approximately 40 days after surgery, before adjuvant treatments. Thirty-four neuropsychological tests were administered in the language, memory, attention, executive functions, and praxis domains. The preoperative percentage of patients with impairment in the considered tests ranged from 0% to 53.3% (mean 20.9%). Despite a general worsening at early follow-up, a significant recovery was observed at late follow-up. Preoperative performances in language and verbal memory tasks depended on the joint effect of tumor volume, volume of surrounding edema, and tumor localization, with major deficits in patients with left lateralized tumor, especially insular and temporal. Preoperative performances in attention and constructive abilities tasks depended on the joint effect of tumor volume, volume of surrounding edema, and patient age, with major deficits in patients ≥ 65 years old. Recovery at late follow-up depended on the volume of resected tumor, edema resorption, and patient age. Longitudinal neuropsychological performance of patients affected by high-grade glioma depends, among other factors, on the complex interplay of tumor volume, volume of surrounding edema, tumor localization, and patient age. Reported results support the definition of criteria for surgical indication based on the above factors. They may be used to propose more customized surgical, oncological, and rehabilitative strategies.