Health-related quality of life (HRQoL) in patients with chronic diseases is an important tool to measure patient-reported health outcomes and evaluate the usefulness of treatment, management, and rehabilitation programs. Patients with chronic diseases are more likely than those without to experience psychological problems such as depression, anxiety, and stress, all of which can affect HRQoL. This study evaluated the impact of psychological problems such as depression, anxiety, and stress on HRQoL in people with and without chronic diseases in South Korea. The study’s descriptive survey included 501 participants (191 with and 310 without chronic diseases). Data were collected using structured questionnaires between April and May 2021. The general characteristics, DASS-21, and HRQOL of this study were analyzed using descriptive statistics. Differences in DASS-21 and HRQoL based on general characteristics were analyzed using t tests and ANOVA. The study analyzed the factors influencing the participants’ HRQoL using stepwise multiple regression analysis with SPSS Win 27.0. HRQoL was generally lower for patients with chronic diseases than for patients without. In patients with chronic diseases, the major variables affecting HRQoL were depression (β = −0.244, t = −3.582, P < .001), exercise (β = 0.201, t = 2.927, P = .004), and economic status (β = −0.150, t = −2.184, P = .030), of which depression was the most influential. These variables explained 12.5% of the variance in the regression model for total HRQoL. These results emphasize the need to explore intervention measures that can reduce depression in patients with chronic diseases and anxiety in patients without chronic diseases to improve their HRQoL. In addition, national efforts are needed to provide economic support, as economic status is an influential factor in HRQoL regardless of the presence of chronic disease. The study’s limitations include the fact that neither did it consider disease severity among chronically ill patients nor did it examine all the variables affecting HRQoL.