Objective To investigate the effect and safety of nimotuzumab combination therapy for locally advanced head and neck squamous cell carcinoma. Methods A total of 72 patients with locally advanced head and neck squamous cell carcinoma, who were admitted to the hospital between July 2021 and June 2023, were selected. According to the treatment methods, the patients were divided into the observation group and the control group, with 36 cases in each group. The control group received apatinib combined with taxol-platinum chemotherapy, while the observation group was treated with nimotuzumab in addition to the regimen of the control group. After 3 cycles of treatment, the objective response rate (ORR), disease control rate (DCR), squamous cell carcinoma associated antigen (SCC-Ag), thymidine kinase 1 (TK1), and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), adverse reactions, one-year overall survival (OS), and progression free survival (PFS) were compared between the two groups. Results The ORR and DCR of the observation group were both higher than those of the control group (P<0.05). After treatment, the SCC-Ag levels of the observation group and the control group were (1.12±0.16) and (1.37±0.25), TK1 levels were (1.65±0.21) and (1.95±0.18), and CYFRA21-1 levels were (5.46±0.75) and (7.02±0.91), respectively. The levels of the observation group were lower than those of the control group (P<0.05). No statistically significant differences were observed in the incidences of leukopenia, erythropenia, thrombocytopenia, neutropenia, transaminase elevation, creatinine elevation, electrolyte imbalance, nausea/vomiting, constipation, hypoalbuminemia, skin and mucosal allergic reactions, and peripheral nerve disorders between the two groups (P>0.05). In the observation group, 3 patients died with a 1-year OS of 91.43% and a 1-year PFS of 71.43%. There were 5 deaths in the control group, with a 1-year OS of 78.79% and a 1-year PFS of 57.58%. Neither group achieved the median OS or median PFS, and the PFS curve of the observation group was superior to that of the control group (P<0.05). Conclusion The combination of nimotuzumab and apatinib and other drugs in the treatment of patients with locally advanced head and neck squamous cell carcinoma can improve ORR and DCR, prolong the PFS, and has good efficacy and safety.