The objective was to evaluate the effects of dietary mannan and β-mannanase supplementation on growth performance and serum acute-phase proteins in nursery pigs. Pigs (n = 480) were blocked by initial body weight (6.6 ± 0.4 kg), and 12 pens per treatment were randomly assigned to one of four treatments in a 2 × 2 factorial arrangement for 28 d. Two levels of dietary mannan (0.4% vs. 2.8%) were offered with and without 0.05% endo-1,4-β-mannanase. Serum was collected (one pig per pen) for haptoglobin and C-reactive protein (CRP) analysis on days 0 and 28. There were no significant interactions between mannan level and β-mannanase supplementation. High-mannan diet decreased average daily gain (P = 0.027) and average daily feed intake (P = 0.024) compared with low-mannan diets with no effect of β-mannanase (P > 0.10). Haptoglobin and CRP were not affected by mannan level or β-mannanase supplementation (P ≥ 0.160). Therefore, dietary β-mannans as high as 2.8% did not induce a systemic innate immune response. Thus, the levels of β-mannan found in practical diets (<2%) are unlikely to induce an immune response; therefore, supplementation of β-mannanase to avoid this response is not warranted.