and promote the development of pulpitis and periapical periodontitis. These bacteria are difficult to eliminate from the root canal systems, leading to persistent infection and poor treatment outcomes. We explored the response of human dental pulp stem cells (hDPSCs) to bacterial invasion and the mechanisms underlying the impact of residual bacteria on dental pulp regeneration. Single-cell sequencing was used to categorize the hDPSCs into clusters based on their response to and . We depicted a single-cell transcriptome atlas of hDPSCs stimulated by or . The most differentially expressed genes in the Pg samples were , , , and , which are related to matrix formation and mineralization, and and , which are related to the cellular response to hypoxia. A cell cluster characterized by high expression levels of and was increased after stimulation. Further signaling pathway analysis showed that hDPSCs prevented infection by regulating the TGF-β/SMAD, NF-κB, and MAPK/ERK signaling pathways. Differentiation potency and pseudotime trajectory analyses showed that hDPSCs infected by undergo multidirectional differentiation, particularly to the mineralization-related cell lineage. Furthermore, can create a hypoxia environment to effect cell differentiation. The Ef samples were characterized by the expression of , which is related to leukocyte chemotaxis, and , which is related to actin. There was an increased proportion of a cell cluster that was similar to myofibroblasts and exhibited significant expression. The presence of promoted the differentiation of hDPSCs into fibroblast-like cells, which highlights the role of fibroblast-like cells and myofibroblasts in tissue repair. hDPSCs do not maintain their stem cell status in the presence of and . They differentiate into mineralization-related cells in the presence of and into fibroblast-like cells in the presence of . We identified the mechanism underlying the infection of hDPSCs by and . Our results will improve understanding of the pathogenesis of pulpitis and periapical periodontitis. Furthermore, the presence of residual bacteria can have adverse effects on the outcomes of regenerative endodontic treatment.