Although some observational studies have linked circulating cytokine levels to asthma, their exact causal relationship(s) remain elusive. To address this knowledge gap, a Mendelian randomization (MR) study was performed to explore potential causal associations between circulating cytokine levels and asthma susceptibility using genetic instrumental variables. To investigate potential causal associations between circulating cytokines and asthma risk, a 2-sample MR analysis was performed using data from European participants from publicly available genome-wide association study summary statistics. Single nucleotide polymorphisms demonstrating significant associations with cytokine levels in previous studies were selected as instrumental genetic variables. A range of complementary MR approaches, including inverse variance weighted, weighted median, MR-Egger, weighted mode, simple mode, and MR pleiotropy residual sum and outlier (i.e., "MR-PRESSO") methods, were implemented to comprehensively investigate causality. Genetically predicted levels of the chemokines RANTES (regulated on activation, normal T-cell expressed and secreted [CCL5]), monocyte chemoattractant protein-1 (MCP-1), and growth-regulated protein alpha (GRO-α) exhibited significant causal associations with reduced asthma susceptibility, as evidenced by odds ratios (OR) of 0.935 (95% confidence interval [CI] 0.895-0.978; P = .003), 0.951 (95% CI 0.916-0.986; P = .007), and 0.968 (95% CI 0.944-0.992; P = .011), respectively. In contrast, beta-nerve growth factor (β-NGF; OR 1.043 [95% CI 1.000-1.087], P = .048), tumor necrosis factor-alpha (TNF-α; OR 1.040 [95% CI 1.001-1.081], P = .042), and macrophage colony stimulating factor (M-CSF; OR 1.032 [95% CI 1.001-1.064], P = .043) conferred increased causal risks for the development of asthma. These causal inferences remain robust across multiple complementary MR approaches, including MR-Egger, weighted median, weighted mode, and simple mode regressions. Sensitivity analyses excluded bias from horizontal pleiotropy. This MR analysis provides initial genomic evidence supporting genetically predicted causal relationships between circulating levels of RANTES, MCP-1, GRO-α, β-NGF, TNF-α, and M-CSF and altered susceptibility to asthma. These findings highlight the potential immunopathogenic roles of these cytokines in the onset and development of asthma.Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.