Curcumin, which is extracted from the traditional Chinese medicine turmeric, is a polyphenolic compound with a variety of biological activities, including immunoenhancement, antioxidant, and antibacterial properties. Singapore grouper iridovirus (SGIV) is a highly contagious viral pathogen that is capable of interfering with the organ function and destroying the immune system of the host, resulting in fish mortality and it has caused significant economic losses to the grouper aquaculture industry. The antiviral activity of curcumin has been demonstrated, but its protective effect against fish virus-induced liver injury requires further investigation. In this study, healthy grouper were infected with SGIV after receiving a curcumin gavage once a day for 15 days and the liver health was assessed. Our results showed that SGIV infection of grouper resulted in severe liver injury as evidenced by histopathological abnormalities, elevated hepatic reactive oxygen species and malondialdehyde, apoptosis and endoplasmic reticulum (ER) stress. On the other hand, we discovered that gavage with curcumin boosted fish immunity and reduced SGIV-induced mortality. Curcumin also ameliorated SGIV-induced liver injury, which might be a result of the modulation of the nuclear factor kappa-B (NF-κB) signaling pathway to reduce liver inflammation, the increase of liver antioxidant levels, the reduction of caspase families-dependent hepatocyte apoptosis, and the relief of liver ER stress by inhibiting heavy-chain binding protein (BIP)/ PKR-like ER kinase (PERK)/ eukaryotic initiation factor 2α (eIF2α)/ activating transcription factor 4 (ATF4) but not inosital-requiring enzyme-1 (IRE1)/ X-box binding protein 1 (XBP1) or ATF6 signaling pathways. This study demonstrated that curcumin possessed strong antiviral activity in fish and highlighted its protective effect on liver of grouper infected with SGIV, providing a theoretical foundation for the functional development of curcumin in aquaculture.