Alpha lipoic acid (α-LA) is a powerful antioxidant, which can reduce oxidative damage and inflammation in the host. In previous research, we found that 600 mg/kg α-LA supplemented in the diet could improve the activity of antioxidant enzymes and regulate the secretion of inflammatory factors in rumen of sheep. However, the mechanism of α-LA driving the antioxidant capacity in rumen of sheep remains unknown. The aim of this current research was to investigate the role of α-LA in antioxidant and inflammatory processes in the rumen of sheep. Transcriptomic and metabolomic analyses were performed to assess the variation of genes and metabolites of rumen epithelial tissue in sheep induced in the LA (600 mg/kg α-LA) group compared with the CTL (0 mg/kg α-LA) group. The results showed that some discovered core genes in the rumen epithelial tissue were negatively correlated with antioxidant activity. G6PD and HK2, the downregulated and upregulated core genes in the comparison of LA/CTL, were enriched in the pentose phosphate pathway (PPP) and the pathways of mannose and oligosaccharide metabolism, respectively. The PPP is a metabolic pathway within cells, primarily functioning to produce nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate. The differential metabolites were enriched in the pathway of 2-oxocarboxylic acid metabolism, which improves the antioxidant capacity of the rumen epithelium by increasing enzymatic activities of SOD. In conclusion, the present study demonstrated that α-LA improved antioxidant activity by regulating PPP and 2-oxocarboxylic acid metabolism. This study will provide a theoretical basis for the application of α-LA in the raising of sheep.