This experiment evaluated the impacts of essential oils (EO) and protease (PRO), independently or in combination, on growth performance, antioxidation, inflammation and intestinal function of weaned pigs. One hundred and sixty weaned pigs (21 d of age, BW of 6.74 ± 0.20 kg) were randomly divided into 4 treatments with 8 replicate pens of 5 pigs per pen. Dietary treatments included the following: 1) control diet (CON), 2) CON with 300 mg/kg essential oils (EO), 3) CON with 500 mg/kg protease (PRO), 4) CON with 300 mg/kg essential oil and 500 mg/kg protease (EO + PRO). On d 8, one pig from each pen was selected for sampling. The remaining pigs were fed for an additional week and growth performance was monitored during this period. Dietary treatments had no marked effects (P > 0.05) on the growth performance of pigs. However, pigs receiving EO diet had higher (P < 0.05) serum glutathione peroxidase (GSH-Px) activity, and tended to decrease (P = 0.063) serum concentration of tumor necrosis factor-α (TNF-α). In addition, pigs receiving EO diet had higher (P < 0.05) abundances of phylum Actinobacteria, and genera Bifidobacterium, and lower (P < 0.05) phylum Bacteroidetes and genera Alloprevotella in colonic digesta. Pigs receiving PRO diet decreased (P < 0.05) the serum concentration of malondialdehyde (MDA) and diamine oxidase activity, increased (P < 0.05) the villus height and the ratio of villus height to crypt depth in duodenum, increased sucrase activity in jejunal mucosa, and also increased the abundance of phylum Actinobacteria in colonic digesta. Furthermore, the synergistic effects of EO and PRO was observed (P < 0.05) for pigs with decreasing serum TNF-α concentration and increasing serum GSH-Px activity. Collectively, the results indicated that dietary supplementation of EO and PRO had no significant effects on growth performance of weaned pigs. EO diet appeared to improve antioxidant activity and intestinal microbiota, while PRO diet improved intestinal morphology and digestive enzyme activity, and there was a synergistic effect of EO and PRO on reducing inflammatory parameters in weaned pigs.