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Simple Summary: The yak (Bos grunniens) is endemic to the Qinghai-Tibetan Plateau, and data on their nutritional requirements are lacking. Previous reports have shown that yaks have a higher nitrogen utilization efficiency than Bos taurus, so we hypothesize that yak diets should have a lower level of dietary crude protein than beef cattle. Two diets with different dietary protein content were designed to investigate the effect of dietary protein levels on yaks in the cold season. The results showed that during the cold season, high protein level could promote rumen microbial protein synthesis, elevate arginine and proline metabolism, purine and pyrimidine metabolism, taste transduction and glutathione metabolism pathways, enhance antioxidant and immune function, and promote growth performance of yak. However, a high-protein diet enhanced the renin secretion pathway, which might increase a yak's water intake. This experiment was aimed to compare the effects of two diets with different protein content on the growth performance, immune indexes, rumen fermentation characteristics and plasma metabolomics of growing yak in the cold season. A total of 24, 2-year-old healthy yaks with similar body weight (142.9 ± 3.56 kg) were randomly allocated to two isoenergetic diets with different protein content (10 vs 14%) according to a non-paired experimental design, and the protein of the diets was increased by increasing soybean meal, rapeseed meal and cottonseed meal. The growth performance experiment lasted 56 days. Four days before the end of the growth experiment, the digestion trial was conducted, and the rumen fluid and plasma was collected for measurement. The results showed that the average daily feed intake (p < 0.001) and average daily gain (p = 0.006) of yak fed a high-protein diet was significantly greater, while the feed conversion ratio was lower (p = 0.021) than that of yaks fed a low-protein diet. Plasma aspartate aminotransferase (p = 0.002), alanine aminotransferase (p < 0.001), malondialdehyde (p = 0.001), tumor necrosis factor-α (p = 0.032) and interferon-γ (p = 0.017) of the high-protein group were significantly lesser, whereas superoxide dismutase (p = 0.004) and interleukin-2 (p = 0.007) was significantly greater than that of the low-protein group. The rumen microbial crude protein (p < 0.047) and crude protein digestibility (p = 0.015) of yak fed a high-protein diet was significantly greater than that of the low-protein group. The metabolomics results showed that yaks fed a high-protein diet were elevated in protein digestion and absorption, arginine and proline metabolism, tryptophan metabolism, purine metabolism, butanoate metabolism, taste transduction, pyrimidine metabolism, pantothenate and CoA biosynthesis, glutathione metabolism and renin secretion pathways. It is concluded that a high-protein diet in the cold season can promote rumen microbial crude protein synthesis, enhance antioxidant and immune function and promote growth performance of yaks. [ABSTRACT FROM AUTHOR]