Background: Kidney failure is a global health problem with a worldwide mean prevalence rate of 13.4%. Kidney failure remains symptomless during most of the early stages until symptoms appear in the advanced stages. Kidney failure is associated with a decrease in health-related quality of life (HRQOL), deterioration in physical and mental health, and an increased risk of cardiovascular morbidity and mortality. This study aimed to evaluate the factors associated with decreased HRQOL and other factors affecting the overall health of patients. Another objective was to measure how medication adherence and depression could affect the overall HRQOL in patients with kidney failure. Methodology: The study used a prospective follow-up mix methodology approach with six-month follow-ups of patients. The participants included in the study population were those with chronic kidney disease grade 4 and kidney failure. Pre-validated and translated questionnaires (Kidney Disease Quality of Life-Short Form, Hamilton Depression Rating Scale Urdu Version, and Morisky Lewis Greens Adherence Scale) and assessment tools were used to collect data. Results: This study recruited 314 patients after an initial assessment based on inclusion criteria. The mean age of the study population was 54.64 ± 15.33 years. There was a 47.6% male and a 52.4% female population. Hypertension and diabetes mellitus remained the most predominant comorbid condition, affecting 64.2% and 74.6% of the population, respectively. The study suggested a significant (p < 0.05) deterioration in the mental health composite score with worsening laboratory variables, particularly hematological and iron studies. Demographic variables significantly impact medication adherence. HRQOL was found to be deteriorating with a significant impact on mental health compared to physical health. Conclusions: Patients on maintenance dialysis for kidney failure have a significant burden of physical and mental symptoms, depression, and low HRQOL. Given the substantial and well-known declines in physical and psychological well-being among kidney failure patients receiving hemodialysis, the findings of this research imply that these areas related to health should receive special attention in the growing and expanding population of kidney failure patients.