Yeast hydrolysate (YH) is rich in amino acids, small peptides, B vitamins, glutathione, and nucleotides, which makes it a possible substitute for spray-dried plasma powder (SDPP). This research was conducted to estimate the application of YH instead of SDPP in creep feed of weaned piglets. The experiment had four treatment groups: (1) basal diet (CON group), (2) CON + 4% YH (YH group), (3) CON + 2% YH + 2% SDPP (SY group), and (4) CON + 4% SDPP (SDPP group). Growth performance, biochemical parameters, immunoglobulin levels, and intestinal tissue morphology were measured. No substantial difference in growth performance between the YH, SY, and SDDP groups was found; however, compared with the CON group, the performance of these three groups was substantially improved. The contents of serum globulin and ALP in the CON group were markedly decreased compared to the other groups, but the AST level was substantially increased. The IL-10 concentration in the other groups was substantially higher than the CON group, and the highest content was in group YH; the TNF-α content showed an opposite trend. The levels of serum IgG and IgA in the CON group were the lowest among all groups. There were substantial differences among the groups in villi height and crypt depth in the duodenum, jejunum, and ileum. The results showed that YH effectively increased IL-10 concentration and decreased TNF-α level to promote intestinal development, while not differing from SDPP in terms of growth performance.