This study evaluated the efficacy, safety, and quality of life (QoL) measure of transdermal fentanyl (TDF) for moderate-to-severe pain due to oral mucositis caused by chemoradiotherapy in patients with advanced nasopharyngeal carcinoma (NPC). Patients with NPC who experienced moderate-to-severe oral mucosal pain during chemoradiotherapy (n=78) received TDF for pain relief. Pain relief and QoL were compared before and after treatment. The mean numeric rating scale score was reduced from 7.41±0.96 before treatment to 5.54±0.86, 3.27±0.73, 2.88±0.62, and 2.82±0.68 on days 1, 4, 7, and 10, respectively, after treatment (P<0.001). Karnofsky performance status and SPAASMS (Score for pain, Physical activity levels, Additional pain medication, Additional physician/emergency room visits, Sleep, Mood, and Side effects) scores showed significant improvement after treatment, indicating an improved QoL of patients (both P<0.001). The most common adverse reactions were nausea and vomiting (10.26%). No serious life-threatening adverse events and no symptoms of drug withdrawal were observed. TDF is effective, safe, and improves QoL in treating pain due to oral mucositis caused by chemoradiotherapy in NPC patients.