Background: Irrational health anxiety increases due to insufficient information about COVID-19 and misinterpretation of allergy symptoms in favor of COVID-19. The disease increases the caregiver burden in informal caregivers and, subsequently, causes physical and mental disorders for them and negatively affects the provision of care for patients. Objectives: This study aimed to examine the relationship between health anxiety and caregiver burden in informal caregivers of patients with COVID-19. Methods: In this cross-sectional and correlational study, the convenient sampling method was adopted to select 340 informal caregivers of patients with COVID-19 who were discharged during the last three weeks of hospitalization in Vasei Hospital of Sabzevar City, Iran, in 2021. To collect the required data, the online links of the demographic information questionnaire, Salkoviskis's short health anxiety inventory (SHAI), and Novak and Guest's Caregiver Burden Inventory (CBI) were sent to the subjects through messengers. The data were analyzed using SPSS 22 as well as descriptive and analytical statistics. Results: According to the results, the mean caregiver burden score in informal caregivers of patients with COVID-19 was 69.72 ± 14.91, and the mean health anxiety score was 16.22 ± 8.24. Pearson's test results were indicative of a significant relationship between caregiver burden and health anxiety (P < 0.001). Conclusions: Since a significant relationship was found between health anxiety and caregiver burden in informal caregivers of patients with COVID-19 in this study, it was argued that the health of informal caregivers was an important health issue certainly deserving serious attention of the health service providers.