End-Stage Renal Disease (ESRD) constitutes the final, irreversible stage of chronic kidney disease (CKD), characterized by the complete loss of renal function and dependence on renal replacement therapies such as haemodialysis or transplantation. The global prevalence of ESRD has reached alarming proportions, driven largely by the escalating incidence of diabetes mellitus, hypertension, and metabolic disorders associated with urbanization and aging populations. According to the Global Burden of Disease Study (2019), CKD ranked as the tenth leading cause of death worldwide, accounting for approximately 1.43 million deaths—a striking 29% increase from 1990. In India, an estimated 1.2 to 1.5 lakh new ESRD cases arise annually, yet limited economic and infrastructural resources hinder equitable access to dialysis and transplantation services. Beyond the physiological deterioration, ESRD profoundly impairs patients’ physical, emotional, and social well-being, while nonadherence to complex medication regimens exacerbates morbidity and mortality. Understanding the interaction between clinical factors, medication adherence, and quality of life (QoL) is therefore critical for designing effective, patient-cantered interventions. The present study was a cross-sectional observational analysis conducted over six months (January–June 2025) in the Department of Nephrology at Government General Hospital, Kurnool, with the objective of exploring the prevalence, clinical profile, medication adherence, and quality of life among patients with ESRD undergoing maintenance haemodialysis. A total of 105 participants aged eighteen years and above, diagnosed with stage 5 CKD and receiving haemodialysis, were enrolled after obtaining informed consent. Data were collected using a structured patient proforma capturing demographic details, comorbidities, symptoms, and lifestyle habits. Medication adherence was assessed using the Morisky 8-Item Medication Adherence Scale, while quality of life was evaluated through the Missoula-VITAS Quality of Life Index. Descriptive and inferential statistics were performed using Microsoft Excel, with results expressed as means, percentages, and standard deviations. Among the 105 patients, 59 (56.2%) were male and 46 (43.8%) female, with the highest representation in the 46–55-year age group (24.8%). Hypertension emerged as the predominant comorbidity (47.6%), followed by combined hypertension and diabetes mellitus (24.8%). The most frequently reported symptoms were fatigue (85.7%), muscle cramps (64.8%), and pruritus (57.1%). Analysis of social habits revealed that 49.2% of males consumed alcohol, 45.8% engaged in both smoking and alcohol use, while 10.9% of females reported drug abuse. Medication adherence levels were moderate in 58.1% of participants, low in 22.9%, and high in only 19%, indicating substantial adherence challenges. QoL assessment revealed higher mean scores in interpersonal (4.2) and well-being (3.9) domains, while symptom (2.1) and transcendence (2.3) domains reflected significant physical and existential distress. A consistent association was observed between lower adherence and poorer QoL scores. This study underscores that ESRD in the Indian context predominantly affects middle-aged males with hypertension and diabetes as principal etiologies. Despite relatively stable interpersonal and emotional functioning, patients face considerable symptom burden, functional decline, and suboptimal medication adherence. These findings highlight the need for integrated, multidisciplinary care models that combine pharmacological optimization, adherence counselling, and psychosocial support to enhance clinical outcomes and overall well-being. Future longitudinal, multicentric studies should further elucidate the causal pathways linking adherence, symptom burden, and quality of life, thereby guiding policy and practice toward comprehensive, patient-centric nephrology care.