Metastatic head and neck tumors, especially metastatic head and neck squamous cell carcinoma, have a poor prognosis and are complex to treat. Although chemotherapy remains the standard first-line treatment option, it is often associated with tumor resistance and side effects. The aim of this retrospective cohort study was to evaluate the efficacy and safety of the combination of panitumumab and paclitaxel in the treatment of metastatic head and neck tumors. The study divided patients into experimental (panitumumab with paclitaxel + cisplatin treatment) and control (paclitaxel + cisplatin treatment) groups, with the primary assessment of objective remission rate and the secondary endpoints of disease control rate, progression-free survival (PFS), and overall survival (OS). The results of the study showed that there was no significant difference in short-term efficacy between the experimental group and the control group (P > .05), but the PFS (median value: 10.2 months) and OS (median value: 15.4 months) of the experimental group were significantly better than those of the control group (median value of PFS: 8.1 months, median value of OS: 11.8 months), and the difference was statistically significant (P < .001). The incidence of adverse events was higher in the experimental group than in the control group, especially in electrolyte disorders and skin rash, and the difference was statistically significant (P < .05), but most of these adverse events were tolerable. In conclusion, the combination of panitumumab and paclitaxel was associated with prolonged PFS and OS in patients with metastatic head and neck tumors, with manageable safety and tolerability compared to standard chemotherapy. These findings suggest that this regimen may represent a potential treatment option and warrant further validation in prospective, randomized studies.