Caregiving for dependent older adults presents significant health and occupational challenges, particularly in rural Thailand. This study examines predictors of health-related quality of life (HR-QOL) among in-home caregivers, focusing on health promotion, non-communicable diseases (NCDs) prevention, and occupational health practices. An analytic cross-sectional study was conducted among 701 caregivers across 23 districts in Nakhon Si Thammarat, southern Thailand. Data were collected through structured questionnaires assessing socio-demographics, health behaviors, working conditions, and HR-QOL using the Thai SF-36V2. Stepwise regression analysis identified key predictors of HR-QOL. Our findings indicate that most caregivers were female (81.5%), middle-aged (mean age: 47.7 years), and had moderate education levels. Over half experienced moderate exposure to occupational hazards, including physical, biological, ergonomic, and psychosocial risks, contributing to job strain, inadequate rest, and strained relationships. HR-QOL scores suggested that a significant proportion of caregivers had moderate to poor quality of life, particularly in physical health domains. Stepwise regression analysis showed that better self-reported health promotion behaviors and occupational hazard prevention practices were positively associated with HR-QOL, whereas the presence of NCDs had a negative impact. These findings highlight the need for targeted interventions to enhance caregivers' well-being and inform public health strategies for strengthening community-based care systems.