Frequent and improper use of herbicides disrupts a plant's metabolism, causing oxidative stress that degrades crop quality. However, few studies have examined the inhibitory effects of herbicides on plant growth and defense mechanisms in terms of their impact on soil quality and crop rhizosphere. Therefore, the current study investigated the detrimental impacts of six typical and multilevel herbicides on the microbial community and signal molecules in the soil as well as on the levels of hormones and secondary metabolites in wheat seedlings. Interestingly, bensulfuron-methyl, terbutylazine (TBA), and 2,4-D butylate significantly induced oxidative damage while reducing the number of phytohormones (salicylic acid and jasmonic acid) and secondary metabolites (tricin, quercetin, and caffeic acid) in the roots and leaves compared with the controls, isoproturon, fenoxaprop-p-ethyl, and pretilachlor. At twice the recommended levels (2×), they also decreased the microbial α diversity and, in particular, the abundance of Gammaproteobacteria, Alphaproteobacteria, Actinobacteria, Bacteroidia, Verrucomicrobia, Bacilli, Acidimicrobiia, Deltaproteobacteria, and Gemmatimonadetes by disrupting the level of enzymes (e.g., urease and sucrase) and metabolites (indole-3-acetic acid, salicylic acid, apigenin, 4-hydroxybenzoic acid, DIMBOA, and melatonin) in the rhizosphere soil. Overall, significant exposure to herbicides may inhibit wheat growth by disturbing the microbial composition in the rhizosphere soil and the distribution of secondary metabolites in wheat seedlings.