The complement system is an evolutionary and crucial component of the innate immune response, which is key to detecting and removing invading pathogens. C1q-domain-containing proteins (C1qDC), as the first subcomponent of the classical pathway in the complement system, can bind immune complexes and activate the classical pathway. Although recent advances in many species have reported the characterization and functional roles of C1qDC in innate immunity, systematic knowledge of C1qDC is still lacking in Pinctada fucata. In this study, the phylogenetic relationship, sequence structure, motif composition, chromosome location, and expression pattern of identified C1qDC genes from the sequencing data of the whole genome of P. fucata were analyzed. The results showed that 285 C1qDC genes were identified and divided into five groups. C1qDC genes have been studied in many species, but the transcript number varies greatly among different species. In previous studies, 232, 335, and 476 C1qDC genes were identified in Mytilus galloprovincialis, Crassostrea gigas, and Crassostrea virginica, respectively. The transcript numbers are far more than that of C1qDC genes in fish and humans, and this is likely related to the lack of adaptive immunity of invertebrates and a weak ability of bivalves to resist adverse external environment and pathogens. The massive gene family expansion has occurred in bivalve evolution and is also common in the bivalve genomes. Structure analysis revealed that all the C1qDC proteins of P. fucata contained motif 1 and were randomly distributed on 14 chromosomes. Additionally, 68 pairs of tandem duplication and one pair of segmental duplication events were found. The higher synonymous substitution rate relative to the non-synonymous rate observed in P. fucata evoked C1qDC genes to evolve under purification selection. Some C1qDC genes showed high levels of polymorphism and were driven by selective pressure to fight off the noxious pathogens. Adaptive evolution of sequence polymorphism likely reflected the coevolution or interplay of host and pathogen. Recent research showed that C1qDC mainly functions as a pattern recognition receptor to mediate cell phagocytosis and agglutination via directly interacting with the receptor on the cell outer membrane. According to the transcriptome data, 56 C1qDC genes (32 upregulated and 24 downregulated) were significantly differentially expressed after the Vibrio alginolyticus challenge. Additionally, real-time PCR was implemented for eight randomly selected C1qDC genes, and agreement was confirmed between the high-throughput sequencing and real-time PCR data. The expression of the C1qDC genes increased in the hemocytes of P. fucata, which indicated that C1qDC might be involved in the immune response related to V. alginolyticus infection. These results provide a theoretical basis for further analysis of the evolutionary pattern of the C1qDC genes and the regulatory roles in the immune response in bivalves.