Simple Summary Yaks (Bos grunniens) are one of the most remarkable domestic animals; however, they generally suffer from malnutrition for almost 8 months of the year, which results in yaks displaying a circannual rhythm with seasonal changes. Yaks are ruminant animals whose utilization of dietary nitrogen efficiency is only about 15.9-19.0%; a large amount of N is excreted in feces and urine. A nutritional method could be taken to improve the utilization rate of dietary nutrients and regulate the synthesis of protein. Methionine makes up the first two limiting amino acids in a corn-soybean-meal-based diet for ruminants; therefore, we added the methionine analogues to the diet to investigate its role in yaks, eventually to find an efficient way to feed yaks. This experiment was conducted to investigate the effects of methionine analogues 2-hydroxy-4-methylthio butanoic acid isopropyl ester (HBMi) on growth performance, nutrient apparent digestibility, serum metabolite, serum free amino acids, and rumen fermentation parameters of yaks. Twenty-four male Maiwa yaks (252.79 +/- 15.95 kg) were randomly allocated to four dietary treatments: basic diet (CON), or three HBMi (MetaSmart (MS); Adisseo Inc., Antony, France) supplementation treatments: MS1 (5 g), MS2 (10 g), and MS3 (15 g). The results showed that the increase in the supplemented MS levels linearly increased the average daily gain (p < 0.05), while the serum alkaline phosphatase activity and malondialdehyde content were increased when yaks were fed with 15 g/d MS (p < 0.05). The diet supplemented with MS linearly increased the percentages of glutamic acid and proline, and linearly or quadratically decreased the percentages of isoleucine, phenylalanine, and valine (p < 0.05). Furthermore, supplementation of 10 g/d and 15 g/d MS increased ruminal microbial crude protein (p < 0.05). The ratio of acetate to propionate in the MS2 group was lower than those in CON and MS1 groups (p < 0.05). In summary, a diet supplemented with 10 g/d MS could be an effective way to improve the growth performance of fattening yaks without negative effects.