Deoxynivalenol (DON) is one of the most common mycotoxins in animal feed worldwide and causes significant threats to the animal health. Increased use of plant ingredients in aquaculture feeds increased the risk of mycotoxin contamination. To evaluate the effects of dietary deoxynivalenol (DON) on growth performance, immune response and intestinal health of turbot and the mitigation efficacy of yeast cell wall extract (YCWE) toward DON, nine isonitrogenous and isolipidic diets were formulated: Diet 1 (control): No DON added; Diets 2–5 or Diets 6–9: 0.5 or 3.0 mg added DON/kg diet + 0%, 0.1%, 0.2%, or 0.4% YCWE, respectively. Results showed that Diet 6 (3 mg/kg DON, 0% YCWE) significantly decreased weight gain, specific growth rate and feed efficiency ratio of fish and reduced immunoglobulin M and complement 4 concentrations in serum. Fish fed Diet 6 presented morphological alterations, lower activity of superoxide dismutase, catalase and total antioxidant capacity but higher malondialdehyde content, lower claudin-4 and occludin expression but higher interleukin-1β expression in intestine. Besides, Diet 6 decreased the abundance of potential helpful bacteria but increased the abundance of potential pathogens in intestine. While, dietary YCWE, especially Diet 8 (3 mg/kg DON, 0.2% YCWE) and 9 (3 mg/kg DON, 0.4% YCWE), markedly improved growth performance and immune response and enhanced the intestinal health of turbot. In conclusion, dietary YCWE could mitigate the toxic effects induced by DON in turbot, and could be used as an effective strategy to control DON contamination in fish feed.