The present study evaluated the impact of chronic herbicide (oxyfluorfen; OXY) exposure on catfish, Clarias gariepinus, in terms of growth, hematobiochemical parameters, immune response, antioxidant- and immune-related gene expression, and resistance to monogenean parasites, Quadriacanthus aegypticus. In addition, the protective role of Wormwood, Artemisia cina (AC) against OXY exposure through diet inclusion was also analyzed. The catfish fingerlings were exposed to OXY (1.16 mg/L) for 60 days and fed diets without AC supplementation (control) and with 5% AC supplementation. The results demonstrated that exposure to OXY stunted growth; decreased survival, erythrograms and leukograms, serum protein, and acetylcholinesterase; and negatively altered the antioxidant status. On the contrary, AC supplementation significantly reduced OXY’s negative impacts on growth and hematological, biochemical, and antioxidant balance. In addition, exposure to OXY markedly increased levels of biomarkers of hepatorenal damage, stress indicators, and DNA damage, which were alleviated with AC supplementation. OXY exposure induced immunosuppression manifested by a decrease in lysozyme activities, complement c3, nitric oxide levels, and phagocytic activity. Furthermore, exposure to OXY negatively regulated the expression of immune-antioxidant genes (CAT, GPX1, SOD1, GST, and TGF-Β1). However, it upregulated the expression of CYP1a, IL-1β, and TNF-α in the liver, anterior kidney, and intestine of C. gariepinus. Meanwhile, the addition of AC to the OXY-exposed fish diets notably restored immune components and remedied the altered immune-related gene expressions. Likewise, the AC supplementation significantly alleviated the OXY-induced reduction in the fish survival rate after Q. aegypticus challenge. Accordingly, AC dietary supplementation in catfish diets could alleviate the negative impact of exposure to OXY on growth performance, physiological status, and some immune-antioxidant-related gene expression.