Background <p>Migraine, a complex neurovascular disorder, is closely associated with neuroinflammation and immune dysregulation. However, the high heterogeneity of immune cell populations means that the specific cellular immune mechanisms driving migraine susceptibility remain unclear.</p> Methods <p>We integrated single-cell expression quantitative trait locus (sc-eQTL) data by applying single-cell Mendelian randomization (Mendelian randomization applied at single-cell resolution, scMR) and colocalization analyses to systematically explore immune-mediated regulatory mechanisms underlying migraine and to identify potential therapeutic targets.</p> Results <p>We assessed the causal effects of 9,117 unique sc-eQTLs on migraine across 14 immune cell types. Four genes (<i>PRDM11</i>, <i>VIM</i>, <i>FGFRL1</i>, <i>C6orf25</i>) were identified as high-priority targets. Colocalization analysis revealed a high probability (posterior probability PP.H4 &gt; 0.90) that these genes share causal variants with migraine genome-wide association study (GWAS) signals. Single-cell RNA sequencing (scRNA-seq) analyses revealed differential expression patterns of these genes across cell types and migraine-related states. Safety assessments based on phenome-wide association studies (PheWAS) showed a low risk of off-target effects in multiple body systems, thus supporting their safety as therapeutic targets. Mapping these targets to a database of known drugs identified three repurposable drug candidates (one approved and two investigational) with therapeutic potential for migraine.</p> Conclusions <p>This study establishes an extensible multi-omics analytical framework, providing novel insights into the immunogenetic basis of migraine. Furthermore, it successfully identified repurposable candidate drugs targeting key pathogenic genes, offering new perspectives for developing novel immunomodulatory therapeutic strategies for migraine.</p> Graphical Abstract <p></p>