Background Caring for patients with dependency is a burden on primary caregivers, which impacts them economically, socially, and psychologically. The perception of caregiving and the psychological state associated with it further contribute to these effects. Objectives This cross-sectional analytical study aimed to study the socioeconomic and caregiving burden factors associated with the Quality of Life (QOL) of dependent patients’ caregivers in the Northeastern region of Thailand. Methodology A total of 1,335 dependent patients’ caregivers aged 18–59 years in the Northeastern Region of Thailand were selected by multistage random sampling to respond to a self-administered structured questionnaire. The Generalized Linear Mixed Model (GLMM) was performed to identify socioeconomic and caregiving burden factors associated with QOL while controlling the effects of covariates, presenting Adjusted Odds Ratio (AOR) and 95% Confidence Intervals (CI). Results Among 1,335 dependent patients’ caregivers, more than half of them had poor QOL (58.05%; 95% CI:39.28 - 44.65). Factors associated with poor QOL were age 46-59 years (AOR=4.30; 95% CI: 2.84-6.51, p-value<0.001), insufficient financial status with debt (AOR=5.89; 95% CI: 3.85-9.01, p-value<0.001), low caregiving knowledge level (AOR=2.43; 95% CI: 1.63-3.64, p-value<0.001), average to low attitude caregiving level (AOR=4.45; 95% CI: 3.30-5.99, p-value <0.001), and having depression (AOR = 3.57; 95% CI: 1.93-6.59, p-value<0.001). Conclusion The findings from this study have important implications for healthcare practice and policy—interventions aimed at improving the QOL of caregivers.