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Simple Summary: The yak (Bos grunniens) is a multi-tasking grazing ruminant species playing vital roles for Tibetan nomads living in the Hindu Kush-Himalayan region and the Qinghai-Tibetan Plateau. Yaks are subjected to undernutrition in traditional pasture management systems during long winters due to inadequate forage intakes. This results in animals losing 25.7~30.2% of their live weight. Large ruminant animals have high intakes of feed and water. The utilization of dietary nitrogen efficiency of yaks is only about 25.9%, and a large amount of nitrogen is excreted in their feces and urine. Changes in nutritional measurement could improve the utilization of dietary nutrients and regulate the synthesis of proteins in yaks. Methionine and lysine are the first two limiting amino acids in a corn–soybean-meal-based diet for ruminants; therefore, we added rumen-protected methionine and lysine to low- and high-protein diets and found that the low-protein diet supplemented with rumen-protected methionine and lysine is beneficial for rumen and body health, physiological response, and metabolic status in yaks. This study investigated the effects of the dietary protein level and rumen-protected methionine and lysine (RPML) on the growth performance, rumen fermentation, and serum indexes of yaks. Thirty-six male yaks were randomly assigned to a two by three factorial experiment with two protein levels, 15.05% and 16.51%, and three RPML levels: 0% RPML; 0.05% RPMet and 0.15% RPLys; and 0.1% RPMet and 0.3% RPLys. The trial lasted for sixty days. The results showed that the low-protein diet increased the DMI and feed conversion ratio of yaks. The diet supplemented with RPML increased the activities of IGF1 and INS and nutrient digestibility. The high-protein diet decreased the rumen butyrate concentration and increased the rumen isovalerate concentration. The low-protein diet supplemented with RPML increased the rumen pH and the concentrations of total volatile fatty acids, butyrate and NH3-N; the high-protein diet supplemented with a high level of RPML decreased the rumen pH and the concentrations of isobutyrate, isovalerate, propionate and NH3-N. The low-protein diet supplemented with RPML increased the total antioxidant capacity and glutathione peroxidase activity, along with the concentrations of malondialdehyde and amino acids such as aspartic acid, lysine, cysteine, etc. In conclusion, a low-protein diet supplemented with RPML is beneficial for rumen and body health, physiological response, and metabolic status in yaks. [ABSTRACT FROM AUTHOR]