Background Central nervous system damage is an essential clinical feature that occurs in the early or late stages of syphilis infection. The abnormal enhancement of microglial phagocytosis can cause damage to the nervous system. However, the contribution of abnormally enhanced microglial phagocytosis to the pathogenesis of Treponema pallidum subsp. pallidum (T. pallidum) infection remains unknown. Objectives In this study, we sought to determine the role of recombinant T. pallidum Tp47 in promoting microglia phagocytosis and its associated mechanisms. Methods Microglial HMC3 cells were used to investigate the effect of the Tp47 on phagocytosis and the roles of autophagy and endoplasmic reticulum stress in Tp47‐induced phagocytosis. Results HMC3 cells exhibited obvious phagocytosis when stimulated with Tp47. The levels of P62 degradation, Beclin1 expression and the LC3II/LC3I ratio were significantly elevated, and the fusion of autophagosomes and lysosomes was promoted in Tp47‐stimulated HMC3 cells. Treatment with the autophagy inhibitors 3‐MA and Baf A1 inhibited Tp47‐induced phagocytosis. Meanwhile, the endoplasmic reticulum stress markers PERK, IRE1α, GRP78, ATF4 and XBP1s were upregulated in Tp47‐stimulated HMC3 cells. In addition, we found that TUDCA could inhibit Tp47‐induced expression of IRE1α but not PERK or ATF4. 4‐PBA inhibited TP47‐induced PERK and ATF4 protein expression but did not inhibit IRE1α expression. Attenuation of endoplasmic reticulum stress by administration of TUDCA and 4‐PBA abrogated Tp47‐mediated autophagy. Conclusions These results suggested that Tp47 activated autophagy through two key pathways associated with endoplasmic reticulum stress, PERK/ATF4 and IRE1/XBP1, to promote phagocytosis in HMC3 cells. These findings provided a basis for the understanding of the pathophysiology of neurological disorders that occur during the course of syphilis.