Large yellow croaker (Larimichthys crocea) is one of the main marine aquaculture species in China, but has faced considerable losses due to Cryptocaryon irritans infection. In this study, we successfully established a C. irritans-susceptible population of large yellow croaker by genomic selection technology. We then compared the immune genetic mechanisms of this susceptible population with those of a large yellow croaker population from eastern Fujian in response to C. irritans infection. GWAS identified 44 significant SNPs across 11 QTL regions on different chromosomes associated with C. irritans infection, with most located on chromosomes 1 and 24. Notably, the QTL region on chromosome 1 overlapped with the resistance QTL region mapped in the C. irritans-resistant population previously established by our team, underscoring its crucial role in conferring resistance to C. irritans infection. RNA-Seq analysis revealed significant differences in immune responses between the two groups, with the susceptible group specifically activating the Jak/Stat signaling pathway and upregulating interleukin-related genes, including il11a, il-5r and il-20r. A combined analysis of the GWAS and RNA-Seq data revealed that cspg4 was located in the overlapping QTL region on chromosome 1 associated with resistance. Upon infection, the expression of cspg4 was significantly higher in the susceptible group compared to the control group. As a downstream factor of interleukins, cspg4 may regulate interleukin expression by activating the Jak/Stat pathway, thereby influencing the body's normal immune defense functions. These findings provide new insights into the mechanisms of host-parasite immune responses and highlight potential therapeutic targets.