Epidermal growth factor (EGF) plays an important role in nutrients absorption. However, whether it can be an effective additive to improve the growth performance and nutrients absorption in lipopolysaccharide (LPS) challenged early weaning piglets is still unknown. A 14-days trial was conducted to investigate how EGF attenuates the effect of LPS on the growth performance, nutrient digestibility, microelement absorption of early-weaned pigs, and study the underlying mechanism. A total of 48 early weaned piglets, aged 25 days, were randomly distributed to four groups (control, EGF, LPS and EGF + LPS groups) consisting of a 2 × 2 factorial design. The main factors were the level of LPS (H = high LPS: 100 μg/kg body weight; Z = low LPS: 0 μg/kg body weight) and EGF (H = high EGF: 2 mg/kg diet; Z = low EGF: 0 mg/kg diet). Each group had four replicates and each replicate consisted of three piglets. The results showed that piglets injected with H level significantly decreased the average daily gain (ADG), and significantly increased the feed conversion ratio (FCR) compared with the piglets injected with Z level, while piglets fed H level significantly increased the average daily feed intake (ADFI) compared with the piglets fed Z level ( < 0.05). Piglets injected with H level significantly decreased the apparent digestibility of crude fat compared with the piglets injected with Z level ( < 0.05). Piglets injected with H level significantly increased the concentration of most microelements in the gastrointestinal tract chyme and feces, and significantly decreased the expression levels of most microelement transport-relative genes in the mucosa of gastrointestinal tissues compared with the piglets injected with Z level ( < 0.05). Piglets fed H level significantly decreased the concentration of microelement in the gastrointestinal tract chyme and feces, and significantly increased the expression levels of the microelement transport-relative genes in the mucosa of gastrointestinal tissues compared with the piglets fed Z level ( < 0.05). In conclusion, dietary EGF could attenuate the negative effect of LPS exposure on the apparent digestibility of crude fat and microelement absorption of early-weaning piglets. EGF and LPS influenced the absorption of essential trace element through changing the expression levels of microelement transport-relative genes in the mucosa of gastrointestinal tissues. In the early weaning piglets, EGF can be used as an additive to increase the essential trace elements absorption.