Abstract Background Epidemiological evidence links inflammation to the etiology and pathophysiology of asthma. To assess the causal relationship between circulating inflammation-related proteins and asthma, we performed a two-sample Mendelian randomization (MR) analysis. Methods Protein quantitative trait locis (pQTLs) were derived from twelve genome-wide association studies (GWASs) cohorts on the circulating inflammation-related proteome. Genetic associations with asthma were obtained from a large-scale GWAS, categorized into childhood-onset asthma (COA) and adult-onset asthma (AOA). Bidirectional MR analysis, Bayesian co-localization, and phenotype scanning were employed to confirm the robustness of MR results. Furthermore, pathway enrichment analysis, protein-protein interaction (PPI) network analysis, and molecule docking were conducted to evaluate the druggability of identified proteins and prioritize potential therapeutic targets. These results were further validated in eQTLGen, GTEx Consortium, and two dependent cohorts. Results Collectively, elevated MMP-1 and decreased levels of three proteins (ADA, CD40L, CST5) were associated with an increased risk of both COA and AOA. CXCL6 had an adverse effect specifically on COA. These associations were validated in sensitivity analyses. Apart from CST5, the other proteins interacted with therapeutic targets of asthma medications. Furthermore, therapeutic targeting of three proteins (ADA, CD40L, MMP1) is currently under evaluation, while CST5 and CXCL6 are considered druggable. Molecular docking showed excellent binding between drugs and proteins (ADA and MMP-1) with available structural data. Conclusions This study identified five circulating inflammatory-related protein biomarkers associated with asthma and provided novel insights into its etiology. Drugs targeting these proteins are expected to facilitate future prioritization of drug targets for asthma.