This cross-sectional study aimed to explore the relationships among sociodemographics, health literacy, self-efficacy, social support, health-promoting behavior, and health-related quality of life (HRQOL) in older adults. A total of 240 older adults aged >65 years were recruited from three community senior welfare centers in South Korea. Standardized self-administered questionnaires measuring sociodemographic characteristics, health literacy, social support, self-efficacy, health-promoting behavior, and health-related quality of life were distributed to older adults. Multiple regression analyses with stepwise selection was used to determine the factors affecting health-related quality of life. Factors affecting a higher physical component score of HRQOL were a higher comprehension level of and numeracy in health literacy, physical health-promoting behavior, perceived emotional–informational support, and a lesser number of comorbidities. Factors affecting a higher mental component score of HRQOL were a higher comprehension level of and numeracy in health literacy, self-efficacy, physical health-promoting behavior, perceived emotional–informational support, and a lesser number of comorbidities. To improve HRQOL among older adults, nursing interventions are required to measure health literacy, empower physical health-promoting behavior and self-efficacy, and enhance emotional–informational support from family or other resources.