Our aim, with this study was to evaluate the consumption, performance, quantitative characteristics of carcasses, biochemical profile, plasma levels of ghrelin and leptin, expression of the receptor for ghrelin (GHS-R1a) in the hypothalamus and duodenum, and the number of goblet cells in the duodenum of calves subjected to milk volume restriction and supplemented with 2-hydroxy-4-(methylthio)butanoate acid (HMTBa). We used 21 Holstein-mixed breed calves, aged between 3 and 15 days with an average weight of 36.8 kg, and housed in pens with troughs for hay, concentrate, and water. The study included two consecutive experimental periods (P1 and P2) of 21 days each, with seven days of adaptation to the diet and facilities. The calves were distributed in a completely randomized design in three treatments with seven repetitions. 1 - Control: 6 L of milk/day during P1 and 6 L of milk/day during P2; 2 – RES (milk restriction): 3 L of milk/day during P1 and 6 L of milk/day during P2; 3 - RES + HMTBa: 3 L of milk/day during P1 and 6 L of milk/day during P2 + 3.3 g of HMTBa/day in both periods. HMTBa was supplied in milk, and the amount of concentrated ration and hay provided and leftovers were recorded daily to estimate dry matter (DM) and crude protein (CP) consumption. Mean daily weight gain (DWG), final weight (FW), and feed conversion (FC) were obtained at the beginning and at the end of each 21-day period. Plasma concentrations of ghrelin and leptin, triglycerides, total protein, urea, lactate, creatinine, alkaline phosphatase, and cholesterol were measured for P1 and P2 at the end of each 21-day period. At the end of P2 animals were slaughtered; sections of the duodenum were collected to evaluate the expression of GHS-R1a and quantity of goblet cells; hypothalamus was used to evaluate the expression of GHS-R1a; rumen was used to evaluate the thickness of epithelium, keratin, density, and height and width of ruminal papillae. In P1, total DM consumption, FW, DWG, glucose and triglycerides were lower in the RES and RES+HMTBa groups (P < 0.001). In P2, there was an improvement in the FC of the RES+HMTBa group (compared to Control and RES) and a lower urea concentration in the RES group (compared to Control and RES+HMTBa) (P < 0.001). No differences were observed among groups regarding hormonal concentrations, histological parameters, and GHS-R1a expression in the duodenum and hypothalamus. Therefore, milk restriction combined with HMTBa supplementation promoted greater compensatory gain by a mechanism independent of changes in GHS-R1a expression and hormone levels of ghrelin and leptin.