<p>Purpose: To evaluate the effectiveness of combined intraoral and extraoral photobiomodulation (PBM) in the management of oral mucositis (OM) and xerostomia in patients undergoing head and neck cancer (HNC) treatment. Methods: Seventy-five patients with HNC were included and randomly assigned to 2 groups: those receiving intraoral PBM and a simulated extraoral PBM application (PBMI-SE group, <i>n</i> = 38); and those receiving combined intraoral and extraoral PBM (PBMIE group, <i>n</i> = 37). Quality of life related to OM and xerostomia, OM symptoms, OM grade, and salivary flow rate were assessed. Results were analyzed using the Kruskal-Wallis test (Student-Newman-Keuls). Results: Combined intraoral and extraoral PBM led to a significant improvement in quality of life (OHIP-14, PROMS, and XeQOLS scores) compared with intraoral PBM alone (<i>p</i> &lt; 0.001). From the second week onward, the PBMIE group experienced significantly lower OM grades (<i>p</i> &lt; 0.001) than the PBMI-SE group. Additionally, the PBMIE group showed a significant improvement in both resting and stimulated sialometry from the second collection onward compared with the PBMI-SE group (<i>p</i> &lt; 0.001). Conclusion: Combined extraoral and intraoral PBM improved the quality of life of patients undergoing HNC treatment, particularly in relation to OM and xerostomia. This combined approach effectively controlled OM severity and improved salivary flow, offering a potential treatment option for these patients. Clinical trial registration: This study was registered in Brazilian Registry of Clinical Trials (ReBEC) (RBR-5p2xfzd). First Posted: October 03, 2023.</p>