The effects of yeast-derived protein (YP) on growth performance, intestinal health, and oxidative status of weanling piglets were investigated. A total of 80 weaned piglets (PIC 327 × 1050, 26 ± 2 days old, 6.20 ± 0.10 kg) were randomly allocated into 2 groups, 5 pens per each group and 8 piglets per each pen, receiving control diet and diet with inclusion of 4% YP at the expenses of fish meal (YP diet) for a period of 28 days. The diets were formulated to contain similar nutrient levels. Compared with control, piglets fed YP diet had markedly higher overall average daily growth (+14%, P < 0.05) and lower final feed conversion ratio (−8%, P < 0.01). Concentrations of serum serine, cystathionine, histidine, hydroxyproline, and urea were decreased in piglets fed YP diet (P < 0.05), whereas alanine and aspartate were increased (P < 0.01). Moreover, serum antioxidant enzyme activity (glutathione peroxidase) was markedly increased (+19%, P < 0.01) in piglets fed YP diet relative to piglets fed control diet. In addition, feeding YP diet considerably (P < 0.05) increased the copy numbers of lactobacilli and total bacteria in the colon of piglets at the end of the experiment. Furthermore, the mRNA abundance of innate immunity-related genes (TLR4, NF-κB1, and IL-6) was increased (P < 0.06) in the ileum of piglets fed YP diet. Collectively, results of this study indicated that diet with the inclusion of YP improved growth performance and partially enhanced anti-oxidative capability as well as intestinal innate immunity of weaning piglets.