Phenanthrene (PHE) is a typical polycyclic aromatic hydrocarbon compound that is ubiquitous in the environment and accumulates in aquatic products, thereby posing a risk to food safety. Oligomeric proanthocyanidins (OPC) is widely distributed powerful antioxidants with potent antioxidant and anti-inflammatory properties. This study aimed to evaluate the alleviating effects of dietary OPC on oxidative stress, inflammatory suppression, and tissue damage caused by PHE exposure in loach (Misgurnus anguillicaudatus). In the study, loach was continuously exposed to 2.36 mg/L PHE for 28 days, after which they were fed a basal diet supplemented with 0, 200, 400, or 800 mg/kg OPC. The results displayed that PHE exposure resulted in significantly increased levels of liver health parameters (AST, ALT, COR, LDH, and ADA) compared to the control group (P < 0.05). The PHE-exposed fish showed the lowest levels of antioxidant enzymes (CAT, SOD, GSH, GST, GSH-Px, and GR) and the greatest levels of oxidative stress parameters (ROS and MDA). PHE exposure resulted in down-regulation of nrf2, ho-1, gsh-px, gst, and nqo-1, and up-regulation of keap-1 gene expressions in loach (P < 0.05). Moreover, PHE-induced decreased the levels of immunity indicators (CRP, MPO, C3, C4, IgM, and LYS). An up-regulation of pro-inflammatory genes (nf-κb, il-1β, il-8, il-6, il-12, and tnf-α) and a down-regulation of anti-inflammatory gene il-10 were the consequences of the PHE exposure. In addition, tissues showed histopathological alterations including vacuolization (liver), displaced nuclei (liver), atrophy (gills), glomerular congestion (kidney), and inflammatory cell infiltration (spleen) caused by PHE. Notably, dietary supplementation of OPC augmented immuno-antioxidant parameters, including their key genes, reduced oxidative stress and immunosuppression, and ameliorated tissue damage compared to fish exposed to PHE. In summary, supplementation with 400 mg/kg OPC in the diets could effectively alleviate the oxidative damage and inflammatory response induced by PHE exposure in loach through the Nrf2/NF-κB signaling pathway and enhance the defense ability against toxic substances of loach.