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Abstract Introduction Out-of-pocket (OOP) is among the payment methods in Iran’s health system. The present study aimed to examine the OOP treatment costs for patients with COVID-19 in Iran. Methods A descriptive-analytical, cross-sectional study was conducted in 2021. In this study, the cost records of 550 patients with COVID-19 hospitalized in a referral center of COVID-19 were selected using the stratified random sampling method. The required data were collected using a researcher-made questionnaire. Data were analyzed by t-test, ANOVA, and Pearson’s correlation coefficient in SPSS software version 23 at p = 0.05. Results The total direct costs were 1,037,992.15 US $. Moreover, the shares of patients (OOP), basic insurance, government subsidy, supplementary insurance, discounts, and out-of-government subsidy in the total direct costs were US $ 92,231.21, 746,932.99 US $, 155,127.08 US $, 39,690.25 US $ and 4010.61 US $, respectively. In addition, the results confirmed that there was a positive and significant relationship between the patients’ OOP payments and the length of stay. It also found that the patients’ OOP payments are subject to the type of insurance program and discharge method. Conclusion According to the results, 8.89% of the total direct costs were directly paid out of the patients’ pockets. The research findings confirm the urgent need to make decisions and implement effective interventions for COVID-19 disease by controlling risk factors and exploiting other countries’ successful experiences and international organizations’ recommendations to decrease the prevalence of the infected and consequently reduce the financial pressure of the disease on patients by approving the expansion of the insurance organizations’ role.