Total mixed rations containing corn silage (CS) or forage sorghum silage (SS) were fed to mid-lactation Holstein cows to determine the effects on feed intake, lactation performance, milk composition and fatty acid profile, nutrient digestibility, blood metabolites, rumen microbial N synthesis, and antioxidant status. The experiment was designed as a 2-period changeover (two 28-d periods) trial with 2 diets including CS diet or SS diet and 12 cows. Total replacement of CS with SS had no significant influence on dry matter intake. Substituting CS with SS had no effect on milk production, feed efficiency, and milk concentrations of fat, protein, lactose, and solids-not-fat, whereas yields of milk fat, protein, and lactose were greater for cows fed the CS diet. Blood parameters including glucose, albumin, cholesterol, triglyceride, total protein, urea N, and fatty acids were not affected by the dietary treatments. Apparent digestibility coefficients of dry matter, organic matter, crude protein, ether extract, neutral detergent fiber, and acid detergent fiber were not significantly influenced by the diets. Replacing CS with SS had no effect on total saturated fatty acids and total monounsaturated fatty acids, whereas total polyunsaturated fatty acid percentage was greater with the SS diet. Proportions of C20:0, C18: 3n-3, and C18: 3n-6 were affected by feeding SS. Cows fed CS had a greater amount of urinary purine derivatives. Feeding SS had a positive effect on total antioxidant capacity of blood and milk. In conclusion, SS can be fed to lactating Holstein cows as a total replacement for CS without undesirable effects on animal performance, but with positive effects on antioxidant capacity and polyunsaturated fatty acids of milk. This forage can be an excellent choice for dairy farms in areas where cultivation of corn is difficult due to water shortage.