Lead (Pb) is a widespread toxic element in agricultural soils and Pb accumulation in plant roots represents a potential health risk for human beings. The sweetpotato (Ipomoea batatas L.) is a globally important root crop and one of the leading raw products for baby food processing. Limited information is available about the mechanism by which sweetpotato responds to Pb stress at the molecular level. Understanding the genetic mechanism of Pb uptake is essential for developing management approaches to mitigate Pb uptake in this crop. To address this knowledge gap, RNA-seq was used to characterize the transcriptome and identify differentially expressed genes from Pb-treated and untreated sweetpotato cv. Beauregard. Samples were taken from adventitious root tips at 5, 10, and 15 days after planting (DAP). Transcriptomic analysis revealed 4,077, 5,159, and 3,206 differentially expressed genes at 5, 10, and 15 DAP respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis shows that ABC transporters and sulfur metabolism pathways are upregulated at 5 DAP but are downregulated at 15 DAP, indicating that there may be a threshold in sweetpotato Pb tolerance. The results provide a deeper insight into the species-specific response of sweetpotato to Pb stress which can lead to the development of screening methods and evaluation of management strategies that reduce Pb uptake in this crop.