〔Abstract〕 Objective To investigate the molecular mechanism underlyingPorphyromonas gingivalis(Pg)-induced autophagy in esophageal squamous cell carcinoma(ESCC). Methods After Pg infected KYSE70 cells and KYSE140 cells pretreated with siAtg7 or Chloroquin(CQ), Western blot was used to measure protein levels of Atg7, LC3-Ⅱ/LC3-Ⅰ, and p62; Immunofluorescent confocal imaging analysis was used to detect autophagosome and autolysosome; CCK-8 assay was used to test cell viability; Transwell assay was used for ESCC cell migration and invasion potentials. Likewise, miR-21-5p inhibitor, RASA1 overexpression plasmid, or U0126 were used to block miR-21-5p/RASA1/ERK signaling pathway prior to Pg infection, followed by the aforementioned methods. In addition, immunohistochemistry was used to examine Pg abundance and LC3 protein levels, and RT-PCR was used to evaluate miR-21-5p expression in ESCC and adjacent tissue samples, followed by correlation analyses between Pg and LC3, and Pg and miR-21-5p. Results Pg infected KYSE70 cells and KYSE140 cells showed upregulation Atg7 protein and LC3-Ⅱ/LC3-Ⅰ protein but downregulation of RASA1 protein and p62 protein, enhanced cell proliferation, migration, and invasion as well as immunofluorescent spots of red, green, and yellow in mRFP-GFP-LC3-labeled ESCC cells. Pretreatment with CQ or siAtg7 abolished the above alterations induced by Pg. Consistently, pretreatment with miR-21-5p inhibitor, U0126, or RASA1 overexpression plasmid also blocked Pg-stimulated autophagy. In ESCC samples, Pg abundance was correlated with upregulation of miR-21-5p and LC3. Conclusion Pg promotes autophagy in esophageal squamous cell carcinomaviamiR-21-5p/RASA1/ERK signaling pathway.