Endometriosis is a frequent, chronic, inflammatory gynecological disease characterized by the presence of ectopic endometrial tissue causing pain and infertility. Macrophages have a central role in lesion establishment and maintenance by driving chronic inflammation and tissue remodeling. Macrophages can be reprogrammed to acquire memory-like characteristics after antigenic challenge to reinforce or inhibit a subsequent immune response, a phenomenon termed “trained immunity.” Here, whereas bacille Calmette-Guérin (BCG) training enhances the lesion growth in a mice model of endometriosis, tolerization with repeated low doses of lipopolysaccharide (LPSlow) or adoptive transfer of LPSlow-tolerized macrophages elicits a suppressor effect. LPSlow-tolerized human macrophages mitigate the fibro-inflammatory phenotype of endometriotic cells in an interleukin-10 (IL-10)-dependent manner. A history of severe Gram-negative infection is associated with reduced infertility duration and alleviated symptoms, in contrast to patients with Gram-positive infection history. Thus, the manipulation of innate immune memory may be effective in dampening hyper-inflammatory conditions, opening the way to promising therapeutic approaches. Display omitted •Peritoneal LPSlow memory macrophages exhibit an anti-inflammatory profile•LPSlow-macrophages hamper endometriosis development in mice•The dampening effects of LPSlow-macrophages on endometriotic cells is IL-10 dependent•A history of severe Gram− bacterial infections may alleviate endometriosis in human Macrophages can acquire a memory-like profile upon challenge with low amounts of LPS and mount an anti-inflammatory secondary immune response. Jeljeli et al. show that LPSlow-memory macrophages alleviate endometriosis growth in mice and dampen fibro-inflammatory properties of human endometriotic cells in an IL-10-dependent manner.