Aim: Sepsis remains a leading cause of morbidity and mortality in intensive care units (ICUs), necessitating early diagnosis and risk stratification. This study aims to evaluate the role of hematological and histopathological parameters in the diagnosis and prognosis of sepsis to improve clinical decision-making and patient outcomes. Materials and Methods: A prospective observational study was conducted over 12 months in the ICU of a tertiary care hospital. A total of 120 patients diagnosed with sepsis based on Sepsis-3 criteria were included. Hematological investigations, including total leukocyte count (TLC), neutrophil-to-lymphocyte ratio (NLR), platelet count, and coagulation markers, were assessed at admission and at 24, 48, and 72 hours. Histopathological analyses were performed on tissue biopsies obtained from liver, kidney, bone marrow, and skin in indicated cases. Microbiological cultures were conducted to identify bacterial, fungal, and polymicrobial infections. Patients were categorized into mild sepsis, severe sepsis, and septic shock groups, and clinical outcomes, including 28-day mortality, ICU length of stay, and incidence of multiple organ dysfunction syndrome (MODS) and disseminated intravascular coagulation (DIC), were analyzed. Results: The mean age of patients was 58.60 ± 12.30 years, with a male predominance (65.00%). Leukocyte counts and NLR increased significantly with sepsis severity (p < 0.001), while platelet counts decreased, correlating with the presence of DIC (p < 0.001). Coagulation markers, including PT, aPTT, and INR, were significantly prolonged in severe sepsis and septic shock (p < 0.001). Histopathological findings revealed liver necrosis (55.00%), renal tubular injury (50.00%), and bone marrow suppression (40.00%) in septic shock cases (p < 0.001). Microbiological analysis identified gram-negative bacteria (65.00%) as the predominant pathogens, with a notable increase in fungal infections (20.00%) in severe cases (p < 0.050). Mortality rates increased significantly with sepsis severity, reaching 65.00% in septic shock (p < 0.001), and ICU stay was significantly longer in these patients (18.70 ± 5.20 days, p < 0.001). Conclusion: Hematological and histopathological parameters serve as crucial diagnostic and prognostic tools in sepsis. Increased leukocyte count, elevated NLR, thrombocytopenia, and coagulation abnormalities correlate with disease severity and poor outcomes. Histopathological findings provide valuable insights into organ dysfunction in sepsis, particularly in liver, kidney, and bone marrow involvement. The predominance of gram-negative infections and high mortality in septic shock emphasize the need for early identification and targeted therapeutic interventions.