The present experiment was conducted to investigate the effects of partial substitution of soybean meal (SBM) with fermented SBM (FSBM) on immunophysiological and stress-related parameters in Holstein calves after weaning. Eighteen Holstein calves were randomly assigned to receive either SBM or FSBM (5% of SBM was replaced with FSBM) calf starter and calves were weaned at 42 d of age. It was noted that FSBM contained a lower content of trypsin inhibitor but higher crude protein, amino acids, and small-sized peptides than those of SBM. The group fed FSBM calf starter significantly increased body weight gain and intakes of both feed and milk, when compared with those fed SBM calf starter at 4 wk of age. Calves fed the FSBM calf starter had significantly lower fecal scores than those fed the SBM calf starter during both pre- and postweaning periods. Calves also had better health scores when fed the FSBM calf starter than those fed SBM during the preweaning period. Weaning challenge significantly increased proinflammatory cytokines, tumor necrosis factor α, IL-1β, and IL-6 levels at 1d postweaning (DPW). The TNF-α and IL-6 levels of the SBM group were significantly higher compared with those of the FSBM group at 3 DPW. Acute phase proteins (serum amyloid A and haptoglobin) in the serum were increased after weaning. Concentrations of serum amyloid A and haptoglobin in calves fed FSBM calf starter were significantly lower than those fed the SBM calf starter at 3 and 5 DPW, respectively. The concentration of cortisol was significantly lower in the FSBM group than that of the SBM group at 3 DPW. Weaning stress did not cause drastic changes in the total serum immunoglobulin levels and composition of peripheral lymphocytes. Our results indicate that FSBM may not only improve growth performance, feed intake, and health conditions during the preweaning period, but also alleviate stress responses, which was indicated by reduced induction of stress hormone, proinflammatory cytokines, and acute phase proteins in Holstein calves after weaning.