Background: End-stage renal disease is the final stage of chronic renal failure where there is a progressive irreversible worsening of renal function. This requires dialysis, a technique in which substances move from the blood through a semipermeable membrane and into a dialysis solution (dialysate). It corrects fluid and electrolyte imbalances and removes waste products in renal failure. Hemodialysis (HD) remains an important form of therapy in end-stage renal disease (ESRD) patients. Dialysis is known to have variable effects on various blood components. It has been reported that dialysis lowers the hemoglobin (Hb) level and red blood cell (RBC) count. This study was primarily conducted to determine the differences between various hematological parameters that occur in renal failure patients before and after HD. Materials and methods: This study is a prospective observational study in which we enrolled 51 patients suffering from renal failure and who are on hemodialysis. The following parameters were recorded: Hb, RBC, packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), total leukocyte count (TLC), differential leukocyte count (DLC)—neutrophil and lymphocyte percentage, platelet count, platelet distribution width (PDW), and platelet large cell ratio (P-LCR). Serum creatinine and blood urea were also observed to assess the improvement with dialysis. All parameters were recorded both pre- and postdialysis. Statistical analysis of data was performed. Results: The RBC count, Hb levels, PCV, MCHC, and percentage neutrophils show significant elevation (p-value < 0.05) in samples obtained after dialysis compared to those obtained before dialysis. On the other hand, there is significant decrease in MCV, lymphocyte percentage, and P-LCR in postdialysis samples compared to predialysis samples. The study showed no significant alterations in many parameters like MCH, RDW, platelet count, TLC, and PDW. The biochemical findings were significant decrease in the blood urea and serum creatinine levels postdialysis which was expected and desirable in patients with chronic kidney disease. Conclusion: The effects of dialysis on Hb and RBC parameters have been studied in many studies but they also have conflicting reports. This may be due to the fact that there can be other factors that may have influence on the values of these parameters that may have not been taken into account. We have documented effects on many other parameters as well but studies with larger sample size that take into account confounding factors like position of patient, gender, etc., need to be done to obtain more conclusive evidence.