BACKGROUND: Infertility affects 8-12% of couples globally, manifesting as a complex reproductive disorder with varied causes, negatively impacting emotional, physical, and social well-being. Inflammation is implicated in many diseases, including male and female infertility. METHODS: This study employed Mendelian randomization (MR) with two-sample, bidirectional, and mediation approaches to explore the relationship between circulating inflammatory proteins and infertility. Causal analysis was conducted using inverse variance-weighted (IVW) and MR-Egger regression, supplemented by enrichment analysis, protein-protein interaction (PPI) network exploration, and drug signature analysis. RESULTS: Our findings identified a significant positive correlation between C-X-C motif chemokine 6 (CXCL6) and male infertility, positioning CXCL6 as a potential therapeutic target or biomarker. No causal links were detected between circulating inflammatory proteins and female infertility post-FDR adjustment. Minor mediation effects were observed for metabolites such as androstenediol monosulfate, arachidonoylcholine, and serum phosphate to glycerol ratio. Cytokine-related pathways emerged as significant in both male and female infertility. Gene-drug interaction analysis highlighted the need for further investigation of pioglitazone in treating female infertility. CONCLUSION: This study establishes a potentially causal relationship between CXCL6 and male infertility, suggesting its potential as a drug target or molecular biomarker. The integrative approach combining causal inference with molecular pathway and drug interaction analysis opens new avenues for understanding and treating infertility.