The previous study has been identified that yeast extract (YE) could be a potential substitute for spray-dried porcine plasma (SDPP) as a superior protein ingredient in diets for pigs in terms of the available energy and AA digestibility. This experiment was conducted to test the hypothesis that YE as a partial substitute for SDPP in diet could stimulate the immune responses and improve the performance and nutrient digestibility in weaned pigs. A total of 90 healthy pigs weaned at 28 d of age (8.5 ± 1.2 kg) were assigned into 3 treatments according to sex and weight in a randomized complete block design. The dietary treatments consisted of a negative control diet without YE and SDPP supplementation (NCD), NCD supplemented with 40 g/kg SDPP at the expense of soybean meal (SDPPD) or SDPPD supplemented with 20 g/kg YE at the expense of SDPP (YED). During the 28-d experimental periods, pigs fed YED and SDPPD improved average daily gain (P < 0.05) and feed efficiency (P < 0.05) compared with pigs fed NCD. No statistical differences in performance were observed between YED and SDPPD. The apparent total tract digestibility of crude protein was greater in pigs fed SDPPD and YED than those fed NCD (P < 0.05). Compared with pigs fed NCD, pigs fed YED decreased (P < 0.05) or tended to decrease (P = 0.09) urea nitrogen and diamine oxidase contents in serum. The serum IgG and IgM content was greater in pigs fed SDPPD and YED than those fed NCD (P < 0.05). The SDPPD and YED decreased serum tumor necrosis factor-α in comparison with NCD (P < 0.05). The YED decreased serum interleukin-6 (P < 0.05), and SDPPD increased serum interleukin-10 compared with NCD (P < 0.05). No statistical differences in small intestinal morphology or hindgut volatile fatty acids were detected among the treatments. Accordingly, YE could be a partial substitute for SDPP in diets for weaned pigs in terms of positive growth performance and immune function.