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The aim of this study was to examine the impact of daily calcium propionate (CaPr) supplementation (0 or 20 g/calf) on growth performance, dietary energetics, body fat reserves, serum metabolites, and hematological responses in high-risk beef calves fed diets with varying (50, 60, or 70%) concentrate (CON) levels. In addition, a cost/income analysis of CaPr supplementation was carried out. Forty-eight crossbred bull calves (152.8 ± 1.56 kg body weight and 5.5 months of age) were involved in a fully randomized experimental design employing a 2 × 3 factorial arrangement of treatments. Calves were allocated (n = 8 per treatment) to individual pens (3.14 × 5.25 m) and were subjected to one of the following treatments during 42 d: No CaPr supplementation in diets containing 50, 60, or 70% CON (NoCaPr + 50, NoCaPr + 60, NoCaPr + 70, respectively) or daily CaPr supplementation dosed at 20 g/calf in diets containing 50, 60, or 70% CON (20CaPr + 50, 20CaPr + 60, 20CaPr + 70, respectively). Non-supplemented calves exhibited decreased dry matter intake (DMI) with increasing CON levels in their diets, while CaPr-supplemented calves displayed the opposite effect (interaction, p = 0.04). In calves fed a lower-CON diet (50%), those supplemented with CaPr showed greater average daily gain (ADG, 20.2%, p = 0.05) and lower DMI (2.2%, p = 0.03), resulting in improved ADG/DMI ratio, dietary energy, and energy retention (24.6, 14.4, and 18%, p < 0.05). These effects diminished when calves received diets with 60 or 70% CON but led to a 14.2% increase in rump fat thickness (p = 0.04). Only in non-supplemented CaPr calves, increasing the level of CON from 50 to 70% in the diet increased ADG (21.2%), decreased DMI (2.2%), and improved the ADG/DMI ratio (22.7%), with no impact on dietary net energy utilization. Non-supplemented calves exhibited an increase in lymphocytes as CON levels rose in their diets, whereas CaPr-supplemented calves showed the opposite effect (interaction, p = 0.05). Supplementation of CaPr decreased total protein (TP, p = 0.03) and albumin (ALB, p < 0.01) serum concentrations, with lower concentrations observed in 20CaPr + 50. CaPr supplementation reduced (p = 0.01) total cholesterol (TCHO) levels. An interaction between CaPr and CON level (p = 0.02) was observed since TCHO levels remained consistently low at higher CON levels. Glucose was decreased with increasing levels of CON (p = 0.02) but not (p = 0.85) for CaPr-supplemented calves. NoCaPr + 50 and NoCaPr + 70 increased (p = 0.05) ALB concentration. Gamma glutamyltransferase levels increased (p = 0.05) with increasing CON levels irrespective of CaPr supplementation. Comparing the profit within the same CON level in the diet, CaPr treatments yielded higher income, with the largest difference in profit observed when CaPr was supplemented at 50% CON level (USD 29 more/calf). In conclusion, CaPr supplementation proves to be an effective strategy for enhancing growth performance and dietary energy among high-risk beef calves, resulting in greater economic returns. The groups that received CaPr demonstrated superior profitability, particularly in calves fed diets with lower CON levels. Under the conditions in which this experiment was carried out, the optimal response occurred when the low-CON diet (50%) was supplemented with CaPr.