This study evaluated the effect of diet supplementation with an essential oil blend (13.5% thymol and 4.5% cinnamaldehyde, EO) on growth performance and selected parameters of oxidative stress and antioxidant defence in Escherichia coli challenged piglets. Ninety-six weaned piglets were allocated into 4 experimental treatments (6 replicates per treatment with 4 piglets per replicate) for 35 days arranged in a 2×2 factorial design: diet [a basal diet without additive (CT) or with 50 mg · kg⁻¹ EO] and E. coli challenge [sham (−) or infected (+)]. On day 8, half of the piglets from each dietary group was orally inoculated with 4 ml of E. coli O149:F4 (K88). The E. coli challenge increased the level of malondialdehyde (MDA) in piglet serum on day 9 (P < 0.01), and tended to reduce average daily gain (P = 0.08) and average daily feed intake (P = 0.08) from day 7 to day 35. Dietary EO addition did not affect growth performance but tended to reduce MDA content in piglet serum in comparison with CT group on day 9 (P = 0.07). Neither EO addition nor E. coli challenge influenced antioxidative enzymes (superoxide dismutase and glutathione peroxidase) activity. The obtained results suggest that EO rich in thymol and cinnamaldehyde had tendency to reduce serum lipid peroxidation level by EO addition, however no such effect was observed in piglets challenged by E. coli. So, further studies are needed to confirm the EO influence on systemic antioxidant defence of weaned piglets.