The administration of interferon has improved the antiviral and immunomodulatory abilities of piglets, which is conductive to the prevention of potential diseases or delay the appearance of clinical symptoms. This study aimed to evaluate the effects from administration of recombinant interferon-alpha (IFN-α) on the daily care of piglets. The results were compared to a Chinese herbal drug that was shown to increase serum interferon levels. In addition, the administration routes of oral administration and intramuscular injection were evaluated. Forty (40) piglets with equal age and weight were randomly divided into four groups: control group (group C, without treatment), group H (treated with compound Chinese herbal), group K (administered orally with recombinant IFN-α, 1500 IU per day per piglet), and group J (administered intramuscularly with IFN-α, 4×106 IU per day per piglet). After the treatment of 15 days, both oral and intramuscular treatment of recombinant IFN-α significantly improved the secretion of IFN-gamma (IFN-γ) ( P < 0.05 ), and the effects of intramuscular pathway were faster. In addition, the expression levels of IFN-stimulated genes (MX1 and ISG15) were significantly enhanced ( P < 0.01 ), independently of IFN-α treatment time and serum IFN-γ level. Different from other studies, compound Chinese herbal showed weaker effects on interferon stimulation in piglets. The results indicated that oral administration of recombinant IFN-α improved interferon-induced response of piglets at both serum and molecular levels, which may be applied for improving autoimmunity of piglets.