This study aimed to examine the effects of high-fat diets supplemented with astaxanthin, chlorogenic acid, and bile acid on the growth, lipid accumulation, oxidation resistance, inflammatory response, and liver morphology in Oncorhynchus mykiss cultured in the convection-water cages. Fish were fed five isonitrogenous diets (D1: 20% lipid; D2: 30% lipid; D3: 30% lipid +0.1% BASF astaxanthin; D4: 30% + 0.06% chlorogenic acid; and D5: 30% lipid +0.1% bile acid) for 6 weeks. The results found that fish fed the D2 diet achieved a lower growth, while the optimal growth was identified in D4 diet. The higher crude lipid contents in the whole body were identified in fish fed the D3-D5 diets. Fish fed the high-fat diet showed liver vacuolization and lower superoxide dismutase (SOD) activity and transcriptional levels of NF-E2-related nuclear factor 2 (Nrf2), catalase (CAT), and SOD, as well as higher malondialdehyde content. Supplementing above three additives can reverse above results and enhance the total antioxidant capacity. Besides, the three additives alleviated the inflammatory responses caused by the high-fat diet via inhibiting proinflammatory cytokines. Moreover, high-fat diet reduced the endogenous lipid production and promoted the lipoprotein hydrolysis by increasing the lipoprotein lipase and inhibiting the fatty acid synthesis. The above results showed that three additives could mitigate the negative effects caused by the high-fat diet. Among them, astaxanthin showed the best antioxidant and anti-inflammatory properties and chlorogenic acid could elevate the growth greatest.