The study aimed to determine the quality of life and mental health status of patients with end-stage renal disease on renal replacement therapy at a tertiary government hospital and their primary caregivers who are directly involved in providing care to the patient. This cross-sectional study evaluated the physical, psychological, and social dimensions of 144 participants, comprising 72 ESRD patients on maintenance hemodialysis and 72 primary caregivers, using validated tools (KDQOL, EQ-5D-3L, and HADS). Among the patients, 62.5% experienced mild to moderate anxiety, and 44.45% exhibited mild to moderate depression. Caregivers showed similar rates of anxiety (61.98%), though depression prevalence was lower (23.31%). Employment disparities were evident, with only 15.28% of patients employed compared to 50% of caregivers. The EQ-5D-3L results revealed significant impairments in mobility, self-care, and usual activities among patients, with moderate to severe difficulties reported in a majority. Patients also reported significantly higher levels of pain and discomfort (p = 0.007). Anxiety scores (HADS-A) showed low but significant inverse correlations with emotional well-being and mental health, while depression (HADS-D) showed stronger inverse relationships with general health, social function, and pain. A higher number of maintenance medications correlated with poorer QOL (p < 0.001). The study highlighted the physical and psychosocial needs of patients with end-stage renal disease (ESRD) on hemodialysis, suggesting the need for integrated care models to manage pain, emotional well-being, and depression. Caregiver support programs should address mental health needs while providing financial assistance and respite care.