The study aimed to compare the molecular mechanism of Porphuromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans). With microarray dataset (GSE9723) from Gene Expression Omnibus, differentially expressed genes (DEGs) were identified comparing normal cell samples with A. actinomycetemcomitans-infected and P. gingivalis-infected periodontitis cell samples, respectively (|logFC| > 1, p value <0.01), followed by hierarchical cluster analysis using Cluster software. Network topological features of A. actinomycetemcomitans-related and P. gingivalis-related protein-protein interaction networks, and background network, which included average shortest path length (ASPL), degree, closeness centrality (CC), eccentricity (EC), betweenness centrality (BC) and topological coefficient (TC) were compared using network analysis plugin of Cytoscape, followed by pathway enrichment analysis (p value <0.05) using FISHER hyper-geometric algorithm and calculation of pathway alter scores using LIMMA. Totally, 839 DEGs and 251 DEGs were screened for A. actinomycetemcomitans and P. gingivalis, respectively. A. actinomycetemcomitans-related network had lower ASPL, degree and EC but higher CC and TC (p < 0.01), while P. gingivalis-related network had lower EC but higher CC and BC (p < 0.01) compared to background network. P. gingivalis-related network had lower ASPL, degree and EC, but higher CC than the A. actinomycetemcomitans-related network (p < 0.05). A. actinomycetemcomitans was associated with the pathways relating to endothelial cells function, while neuroactive ligand-receptor interaction and MAPK pathways were important for P. gingivalis, which had higher alter scores in hematopoietic cell lineage, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy pathways than A. actinomycetemcomitans. Genes and pathways of the two pathogens were distinctive. The findings aided in preventing and treating relevant diseases.