ABSTRACT Ficolin‐1 (FCN1, M‐FCN), the key pattern recognition molecule of the innate immune system, possesses a collagen‐like domain and a fibrinogen‐like domain, exhibiting bidirectional immunomodulatory functions that influence immune homeostasis and disease progression. Recent studies reveal that beyond its well‐established roles in pathogen recognition and complement activation, FCN1 orchestrates the balance between pro‐inflammatory and anti‐inflammatory responses, facilitating crosstalk between innate and adaptive immunity. This review synthesises cutting‐edge research to systematically elucidate the multifaceted roles of FCN1 in human diseases, including autoimmune disorders, infectious diseases, tumour, cardiovascular and cerebrovascular disease. We highlight how FCN1 exerts its regulatory effects through diverse mechanisms ranging from pathogen binding and clearance to cytokine secretion modulation and immune cell fate determination, ultimately shaping disease susceptibility, progression and prognosis. By compiling these groundbreaking findings, we propose FCN1 as a pivotal orchestrator of immune responses, providing a theoretical foundation for its translation into diagnostic biomarkers and novel therapeutic targets in precision medicine. This review advocates for the establishment of standardised FCN1 assays and large‐scale clinical validation to accelerate its transformation from bench to bedside.