Purpose One of the most important questions is how the COVID-19 epidemic affects health-related quality of life (HRQOL) in the general population. This study aims to know about the impact of the COVID-19 epidemic on the HRQOL in the general population in Iran.MethodsAn online survey was developed and participants were recruited via social media (What’s up, Telegram) from Fars province residences from 3th to the 20th of November 2020. Data of this cross-sectional study were collected by a researcher-made demographic, EuroQol-5 Dimension (EQ-5D), and Visual Analog Scale (VAS) questionnaires. The multivariate logistic regression model and CLAD Regression was used for the five health dimensions, and the factors associated with the EQ-5D Index were investigated. Results The mean EQ-5D Index and EQ-VAS of the respondents were 0.80 and 77.53, respectively. The most frequently reported problems were pain/discomfort (P/D) (44.17%) and anxiety/depression (A/D) (53.69%). Logistic regression models showed that the risk of P/D among old people, who were worried about getting COVID-19, and the risk of A/D among people with male, having hypertension and asthma diseases, unemployment, having insurance, and worry about getting COVID-19 were significantly high. The results of CLAD regression indicated that low income (very low and low income), having hypertension, and having asthma were inversely associated with the EQ-5D Index score. Data collection through an online questionnaire could be prone to selection bias. ConclusionAccording to the results, the mental health of people, especially those with chronic diseases and low-income must be considered during epidemics or other emergencies.