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Objective: To analyze the hospitalization expenditures and their temporal trends in patients with nasopharyngeal carcinoma (NPC), and evaluate the associated economic burden and influencing factors. Methods: A random sampling survey was conducted in newly diagnosed NPC patients undergoing curative therapy in a grade Ⅲ cancer hospital in Southern China from January 2019 to December 2023 to obtain their hospitalization cost data, the patients with recurrence, metastasis, severe complications or receiving no radical therapy were excluded. The collected data included basic demographics, tumor characteristic, treatment way, payment method, total hospitalization expenditure, and their composition. The primary outcome was the median hospitalization expenditure per case (adjusted to 2023 values using the Consumer Price Index). Univariate and multivariate generalized linear models were used to identify factors associated with hospitalization expenditures. The annual cost composition and temporal trends were analyzed. Results: A total of 788 NPC patients were finally included with an age of diagnosis of (47.0±11.7) years, in whom 598 (75.9%) were from Southern China, 584 (74.1%) were men, and 716 (90.9%) were at advanced stage. The M(Q₁, Q₃) hospitalization expenditure per case was 146 289 (125 083, 178 056) yuan. The median expenditures in 2019, 2020 and 2021 were 150 718, 151 811 and 157 463 yuan, respectively, and the median expenditures decreased to 139 696 yuan in 2022 and 134 621 yuan in 2023. Regarding cost composition, the expenditure for radiotherapy was highest (83 430 yuan, 59.7%), followed by the expenditure for medication (26 580 yuan, 19.0%). Multivariable generalized linear model analysis showed that the median hospitalization expenditure (150 045 yuan) was higher in patients with commercial insurance or public funding than in those with urban resident basic medical insurance (144 524 yuan) (aOR=1.11, 95%CI: 1.06-1.16, P<0.001). Patients in advanced stage had higher expenditures (149 342 yuan) compared with those in early stage (114 476 yuan) (aOR=1.11, 95%CI: 1.03-1.19, P=0.002). Patients receiving comprehensive treatment incurred higher expenditures (148 573 yuan) compared with those receiving radiotherapy alone (99 727 yuan) (aOR=1.33, 95%CI: 1.21-1.47, P<0.001). The median hospitalization expenditures of patients in 2022 (139 696 yuan) and 2023 (134 621 yuan) were lower than those in 2019 (150 718 yuan) (aOR=0.93, 95%CI: 0.88-0.99; aOR=0.87, 95%CI: 0.82-0.93, both P<0.05). Conclusions: The median hospitalization expenditure per case in NPC patients was high with a slight decreasing trend in recent years. Payment method, clinical stage, treatment way, year of hospitalization were the main factors influencing the hospitalization expenditure.