Chronic kidney disease (CKD) significantly affects health-related quality of life (HRQoL), impacting physical and mental well-being. This study aimed to identify the key determinants influencing HRQoL among patients with CKD. A cross-sectional observational study was conducted from July 2022 to March 2023 at the Rajiv Gandhi Cooperative Multi-Specialty Hospital, Palakkad, Kerala, South India, including 154 patients diagnosed with CKD stages 3 to 5. Eligible participants were required to be at least 18 years of age and have a confirmed diagnosis of CKD, specifically stages 3 to 5, with prior treatment. CKD stages were defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines, based on estimated glomerular filtration rate (eGFR) thresholds as follows: Stage 3 (eGFR 30-59 mL/min/1.73 m), Stage 4 (eGFR 15-29 mL/min/1.73 m), and Stage 5 (eGFR < 15 mL/min/1.73 m). Participants were classified into stages based on their most recent stable eGFR value at the time of recruitment. HRQoL was assessed using the European Quality of Life-5 Dimensions-3 Levels (EQ-5D-3L) questionnaire. Chi-square, ANOVA, and multivariate regression were used to analyze associations with EQ-5D-3L domains. Out of 154 participants, 68.8% were male, 91.6% were aged over 50 years, and 63.6% were from rural areas. Most had primary education (55.2%) and were unemployed, retired, or housewives (66.2%). As CKD progressed, comorbidities, particularly diabetes mellitus and coronary artery disease (CAD), increased, with Stage 5 showing the highest prevalence. Clinical markers showed significant declines in the glomerular filtration rate (GFR) (Stage 3: 49.16 ± 7.59, Stage 4: 22.37 ± 3.88, Stage 5: 8.79 ± 1.68) and hemoglobin (Stage 3: 10.45 ± 0.84, Stage 4: 8.88 ± 0.60, Stage 5: 7.12 ± 0.53) and an increase in serum creatinine (Stage 3: 1.72 ± 0.40, Stage 4: 3.21 ± 0.44, Stage 5: 7.05 ± 1.46). HRQoL assessments showed significant declines in mobility, self-care, usual activities, pain, and anxiety/depression with advancing CKD. Mobility issues increased from 61.2% in Stage 3 to 62.0% in Stage 5, with greater difficulties in self-care and usual activities at Stage 5. Pain and anxiety/depression worsened across stages. Multivariate analysis identified female gender, older age (≥50 years), lower education, unemployment, multiple comorbidities, smoking, lack of social support, and advanced CKD stages as significant factors linked to impaired HRQoL. CKD stage 5 (GFR < 29 mL/min/1.73 m) and high serum creatinine (>1.2 mg/dL) were associated with significantly higher odds of impairment in all HRQoL domains. This study highlights that factors such as female gender, older age, lower education, unemployment, multiple comorbidities, smoking, advanced CKD stages, and high serum creatinine levels are associated with reduced quality of life in CKD patients. Conversely, social support acts as a protective factor. The findings emphasize the need for targeted interventions that address both medical care and psychosocial aspects, including lifestyle changes, patient education, mental health support, and community involvement, to improve CKD patients' well-being.