This study aimed to analyze the transcriptome of C. rupestris under Pb2+ stress by using high-throughput sequencing technology, observe the changes of gene expression and metabolic pathway after three and five days under 1.0 and 5.0 mg/L of Pb2+ treatment, and analyze the differentially expressed genes (DEGs) and related functional genes after Pb2+ treatment. Metabolic pathways were revealed through Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results show that DEGs increased significantly with the increase of Pb2+ concentration and stress time. A total of 32 genes were closely related to Pb2+ stress response. GO analysis identified two major transporter proteins, namely, ATP-binding transport protein-related (ABC transporters) and zinc finger CCHC domain containing protein (Zfp) in C. rupestris. Pthr19248, pthr19211, Zfp pthr23002, Zfp p48znf pthr12681, Zfp 294 pthr12389, and Zfp pthr23067 played important roles against Pb2+ toxicity and its absorption in C. rupestris. KEGG pathway analysis suggested that ABCA1, ATM, and ABCD3 were closely related to Pb2+ absorption. Pb2+ stress was mainly involved in metallothionein (MT), plant hormone signal transduction, ABC transporters, and glutathione (GSH) metabolism.