Abstract: This study investigates the roles of 18-hydroxyeicosapentaenoic acid (18-HEPE) and resolvin E1 (RvE1) in the inflammatory responses of head kidney macrophages in large yellow croaker (Larimichthys crocea), addressing inflammation issues in aquaculture. A classical inflammatory models was established by stimulating head kidney macrophages with 50 μg/mL lipopolysaccharide (LPS) for 12h. The effects were evaluated under two experimental conditions: co-incubation with 18-HEPE (500 and 2000 nmol/L) or RvE1 (10, 50, 100 and 500 nmol/L), and pre-incubation with 18-HEPE (0.5h, 2h, 8h and 12h) or RvE1 (0.5h, 3h, 6h, 9h, 12h and 24h), followed by measuring the expression levels of inflammation-related genes il-1β, il-6, il-8, il-10, tnf-α, ifn-γ and cox-2. The results showed that under co-incubation conditions, 500 nmol/L RvE1significantly down-regulated the expression levels of inflammation-related genes il-8 and ifn-γ in a concentration-dependent manner. In pre-incubation experiments, 100 nmol/L RvE1significantly reduced the expression levels of inflammation-related genes il-1β, il-6, il-8, tnf-α and cox-2. However, neither co-incubation nor pre-incubation with 18-HEPE had significant effects on the expression levels of these genes. These findings indicate that RvE1 (but not its precursor 18-HEPE) significantly alleviates LPS-induced inflammatory responses in head kidney macrophages of large yellow croaker, with pre-incubation exhibiting superior anti-inflammatory activity compared to co-incubation. This study expands the theoretical research of fatty acid derivatives in fish and provides new insights for inflammation control in aquaculture animals.