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Background: Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO^®) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules. Methods: In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency “Guidelines on the investigation of Bioequivalence”. The phase I, multicenter, randomized, open-label, crossover, single-dose bioequivalence study enrolled 36 adult patients with glioblastoma multiforme or lower-grade glioma. Each patient received 200 mg/m² Ped-TMZ suspension and TMZ capsules (Temodal^®) on 2 consecutive days, with the order being randomly assigned. Fourteen blood samples were collected up to 10 h post-dosing. Bioequivalence was assessed by comparing the 90% confidence interval for the ratio of the geometric means of maximum TMZ plasma concentration (C_max) and the area under the curve (AUCt). Other endpoints included further pharmacokinetic parameters and safety. Results: Both formulations exhibited a fast in vitro dissolution profile with more than 85% of TMZ dissolved within 15 min. For the bioequivalence study, thirty patients completed the trial as per the protocol. The ratio of Ped-TMZ/TMZ capsule geometric means (90% CI) for AUCt and C_max were 97.18% (95.05–99.35%) and 107.62% (98.07–118.09%), respectively, i.e., within the 80–125% bioequivalence limits. No buccal toxicity was associated with Ped-TMZ liquid formulation. Conclusions: This study showed that Ped-TMZ oral suspension and TMZ oral capsule treatment are immediate release and bioequivalent medicines. There were also no unexpected safety signals or local toxicity (funded by ORPHELIA Pharma; ClinicalTrials.gov number, NCT04467346).