The innate immune system, including the cell-based immunity (mainly apoptosis and phagocytosis) and the humoral immunity (such as pro-phenoloxidase system), is the first defense line of animals against the infection of pathogens in a non-specific manner, which is fine regulated through the gene expression regulations. The microRNAs (miRNAs) are recognized as important regulators of gene expression. To date, however, a comprehensive view about the regulation of innate immunity by miRNAs is not available. To address this issue, the signature miRNAs involved in the innate immunity were characterized in this study. The phagocytosis, apoptosis and phenoloxidase (PO), a key enzyme in the pro-phenoloxidase system, of invertebrate shrimp were activated or inhibited, followed by the small RNA sequencing. The results showed that a total of 24 miRNAs took great effects on phagocytosis, apoptosis or the pro-phenoloxidase system, which were further confirmed by Northern blots. Among the 24 innate immunity-associated miRNAs, 21 miRNAs were conserved in animals, suggesting that these miRNAs might share the similar or the same functions in different species of animals. Based on degradome sequencing and prediction of target genes, it was found that the miRNAs might mediate the regulations of phagocytosis, apoptosis or pro-phenoloxidase system by targeting different genes. Therefore our study presented the first comprehensive view of the miRNAs associated with innate immunity, which would facilitate to reveal the molecular events in the regulation of innate immunity.