Pb stress, a toxic abiotic stress, critically affects maize production and food security. Although some progress has been made in understanding the damage caused by Pb stress and plant response strategies, the regulatory mechanisms and resistance genes involved in the response to lead stress in crops are largely unknown. In this study, the response mechanism of maize to Pb stress, the expression of Pb tolerance genes, physiological and biochemical indexes, the transcriptome, and the metabolome under different concentrations of Pb stress were combined for comprehensive analysis. As a result, the antioxidant system was significantly inhibited under Pb stress, especially under relatively high Pb concentrations. Transcriptome analysis revealed 3559 co-DEGs under the four Pb concentration treatments, which were enriched mainly in the GO terms related to DNA-binding transcription factor activity, response to stress, response to reactive oxygen species, cell death, the plasma membrane and root epidermal cell differentiation. Metabolome analysis revealed 72 and 107 DEMs under T500 and T2000, respectively, and 36 co-DEMs. KEGG analysis of the DEMs and DEGs revealed a common metabolic pathway, namely, flavonoid biosynthesis. An association study between the flavonoid biosynthesis-related DEMs and DEGs revealed 20 genes associated with flavonoid-related metabolites, including 3 for genistin and 17 for calycosin. This study not only provides genetic resources for the genetic improvement of maize Pb tolerance but also enriches the theoretical basis of the maize Pb stress response.