Endometriosis is a complex gynecological condition in which endometrial fragments are implanted outside the uterus, causing pain and infertility. Although immune mediators play a vital role in endometriosis, their exact etiology remains elusive. Using Mendelian randomization (MR), this study aimed to assess the causal relationship between inflammatory proteins and endometriosis.Genetic variants associated with inflammatory proteins were filtered from a genome-wide protein quantitative trait locus study under stringent thresholds. These variants were used as instrumental variables (IVs) to evaluate the causal effects of these inflammatory proteins on endometriosis. A two-sample MR analysis was performed with endometriosis from the UK Biobank as the outcome, and a sensitivity analysis was performed to mitigate potential confounding factors. Analyses were replicated in an independent endometriosis cohort from the FinnGen, followed by a meta-analysis of MR results from both cohorts. Finally, we assessed the causality between inflammatory proteins and the endometriosis subtypes.Independent MR analysis revealed that the genetically higher levels of CXCL5 were linked to a lower chance of having endometriosis. The causal link remained significant in the meta-analysis. Furthermore, the causality of CXCL5 expression has been identified in ovarian and pelvic peritoneal endometriosis.Our MR analysis indicated that CXCL5 was associated with a decreased risk of endometriosis, suggesting that CXCL5 might have a protective effect against endometriosis. This enhances our understanding of the involvement of chemokines in endometriosis pathology and provides insights for future studies to explore the detailed mechanisms underlying CXCL5 in endometriosis.