Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, leading to muscle weakness, paralysis, and eventual respiratory failure. Systemic inflammation, oxidative stress, and impaired oxygen transport have been implicated in disease progression. Hematological biomarkers, such as the neutrophil-to lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), red cell distribution width (RDW), and hemoglobin (Hb), may serve as potential prognostic indicators for ALS. Objectives: This study aimed to evaluate the prognostic value of routine hematological markers (NLR, PLR, RDW, and Hb) in ALS progression. Methodology: A cross-sectional study was conducted in the neurology departments of tertiary care hospitals in Karachi, with 345 ALS patients categorized into early stage and advanced-stage groups. Independent t-tests and Mann-Whitney U tests were used for group comparisons. Pearson’s and Spearman’s correlation coefficients assessed relationships between hematological markers and ALS severity. Multivariate logistic regression was applied to identify independent predictors of disease progression. Results & Findings: NLR and PLR were significantly elevated in advanced-stage ALS patients, indicating systemic inflammation. RDW was also higher, suggesting increased oxidative stress, while Hb levels were lower, reflecting impaired oxygen transport. Correlation analyses confirmed significant associations between these markers and disease severity. Logistic regression identified NLR and RDW as independent predictors of ALS progression. Conclusion: Routine hematological markers provide valuable prognostic insight into ALS progression. Their association with inflammation, oxidative stress, and oxygen transport dysfunction suggests their potential role in disease monitoring. Incorporating these biomarkers into clinical assessments may improve patient stratification and therapeutic decision-making. Further longitudinal studies are needed to validate these findings and explore targeted interventions.