The traditional Chinese medicine (TCM) formula Shegan Mahuang Decoction (SMD) has been used for treating asthma with significant clinical efficacy, but its mechanism of action has not been well investigated. This study aimed to investigate the anti-asthma effects of SMD on ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) in rats and its potential mechanisms using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics combined with Gene Expression Omnibus (GEO) data mining. The results showed that the administration of SMD significantly attenuated OVA-induced lung histopathological changes. OVA-induced elevation of the immunoglobulin (IgE) and interleukin-4 (IL-4) levels was also inhibited by SMD. A total of 28 significantly changed metabolites in plasma were selected from metabolomics analysis. After treatment with SMD, 24 of them were negatively regulated and the related metabolisms were involved in multiple metabolic pathways such as sphingolipid metabolism and arachidonic acid metabolism. The differentially expressed genes (DEGs) were obtained by GEO data mining. The integrated pathway analysis highlighted 11 signaling pathways that were associated with the anti-asthma effect of SMD. Among them, the metabolite-gene-pathway network showed that the peroxisome proliferator-activated receptors (PPAR) signaling pathway might be the most significant one. This study revealed that SMD exerted an anti-asthma effect against OVA-induced AHR via comprehensively modulating the sphingolipid metabolism, arachidonic acid metabolism, and PPAR signaling, which indicated the synergistic effect of multi-component, multi-target, and multi-pathway of TCM in the treatment of the disease. This study expands our understanding of SMD in the treatment of asthma from a metabolomics perspective.