Motor neuron degeneration is a defining feature of amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder. Early diagnosis remains challenging due to the absence of reliable and validated biomarkers. Calprotectin, a well-established inflammatory marker in various neuroinflammatory conditions, has paradoxically been found at reduced levels in the blood of ALS patients in a limited number of studies, raising the hypothesis of immune dysregulation rather than classical neuroinflammation. However, these findings are primarily derived from small patient cohorts and have yet to be independently replicated. This review critically assesses the emerging role of calprotectin in ALS by comparing it with other candidate biomarkers, including vascular endothelial growth factor (VEGF), apolipoprotein A1 (ApoA1), interleukin-8 (IL-8), interleukin-7 (IL-7), and interleukin-10 (IL-10). While calprotectin may reflect a distinct immunological profile, its standalone diagnostic value remains unclear. Nonetheless, its integration into a multi-analyte biomarker panel could enhance diagnostic precision and biological insight. The review also explores underlying immunological mechanisms, including receptor interactions (RAGE, TLR4, CD33), cellular mediators (microglia, lymphocytes, monocytes), and therapeutic implications. Future research should prioritize mechanistic investigation of calprotectin modulation in ALS, longitudinal validation in larger cohorts, and integration within multimodal biomarker frameworks. A better understanding of disease-specific immune alterations may contribute to earlier diagnosis, stratified patient monitoring, and targeted therapeutic development.