Background Malnutrition, in patients with solid tumors, is associated with a worse clinical outcome and about 40% of patients affected by head and neck cancers (HNC) are malnourished at the time of cancer diagnosis. We investigated the potential benefit of a standardized immunonutritional protocol (INP) to patients with HNC receiving major ablative surgery. Methods An observational study was conducted enrolling 199 patients: 50 treated with the INP and 149 with standard enteral nutrition. Complication rates, need for medications, and costs were considered as outcomes. Results INP played a protective role in development of major surgical complications (OR 0.23, p = 0.023), albumin administration (RR 0.38, p = 0.018), and antibiotic duration (p < 0.001) and is cost‐effective in patients with moderate or severe malnutrition (−6083€ and −11 988€, p < 0.05). Conclusions Our study supports the utility of INP, and accurate nutritional screening can help to identify malnourished patients who would receive the most benefits from this protocol.