Abstract Objective: Observational research indicates that immune cells, in conjunction with circulating inflammatory proteins, could serve two functions in the development of delirium, despite the fact that the exact mechanisms remain ambiguous. The objective of this research is to identify the specific pathways through which immune cells trigger delirium and to evaluate the possible function of circulating inflammatory proteins as intermediaries. Methods: A two‐sample Mendelian randomization (MR) analysis was conducted using summary‐level data from genome‐wide association studies, which included 731 immune cells, 91 inflammatory proteins, and their association with delirium. The causal relationships between immune cells, inflammatory proteins, and delirium were systematically assessed through multivariable Mendelian randomization (multivariable MR). Following this, sensitivity analyses were performed using the Cochran Q test to evaluate heterogeneity, alongside MR‐Egger tests to examine pleiotropy. Finally, a two‐step methodology was employed to identify the inflammatory proteins that mediate the impact of immune cells on the onset of delirium. Results Multivariable MR revealed 14 immune cell types that exhibited a causal relationship with delirium, along with 4 inflammatory proteins associated with this condition. Through a two‐step analysis, it was determined that 2 inflammatory proteins mediate the influence of 2 immune cell phenotypes on delirium. Specifically, CD25 on IgD ‐ CD 38 dim is linked to the inflammatory protein LIGHT, which accounts for a mediation percentage of 9.65%. Meanwhile, CD127 on CD45RA ‐ CD4, not Treg, is associated with the inflammatory protein CCL20, showing a mediation percentage of 9.78%. Conclusion: This study conducted a thorough investigation into the causal relationships between immune cells and delirium, while also assessing the role of inflammatory proteins as mediators. The results aid in recognizing individuals who are at an elevated risk for experiencing delirium while also offering novel perspectives for proactive preventive measures and therapeutic strategies within clinical environments.