TP53mutation is associated with cancer progression. Novel strategies to reboot p53 are required to stabilize the disease and improve survival. This randomized placebo-controlled trial investigated safety and efficacy of Nutri-PEITC Jelly (a texture-modified nutritious diet fortified with β-phenethyl isothiocyanate (PEITC) on oral cancer. Seventy-two patients with advanced-staged oral or oropharyngeal cancer were randomly assigned to study and control groups, who consumed 200 g of Nutri-Jelly with and without 20 mg of PEITC, respectively, 5 days/week for 12 weeks. Outcomes, including adverse events, health-related quality of life (HRQOL), progression-free survival (PFS), tumor response, serum p53, and cytochrome c, were measured at 0, 1, and 3 months. Results show that the study group had a higher proportion of participants with improved HRQOL, stable disease, and increased serum p53 levels than those in the control group (p< 0.001). The PFS time in the study group was significantly longer than that of the control group (p< 0.05). Serum cytochrome c levels were non-significantly decreased in the study group. No serious intervention-related adverse events occurred in either group. In conclusion, Nutri-PEITC Jelly intake for 3 months is safe, stabilizes the disease, improves quality of life and progression-free survival, and might re-activate p53 in advanced-stage oral and oropharyngeal cancer patients.