Background <p>Developing effective and safe drug targets for atrial fibrillation/flutter (AF/AFL) is a critical clinical need. As the plasma proteome represents a major source of druggable targets, this study aimed to identify causal protein targets for AF/AFL and assess their potential side effects.</p> Methods <p>A two-sample Mendelian Randomization (MR) study was conducted to evaluate the causal effects of plasma proteins from the UK Biobank Pharma Proteomics Project (UKB-PPP) and the deCODE database on the risk of AF/AFL. The MR findings were further confirmed through Bayesian colocalization and Transcriptome-Wide Association Studies (TWAS) analyses. Furthermore, phenome-wide association study (PheWAS) was conducted to depict potential side effects of druggable targets, and Multivariable MR (MVMR) explored the potential mediators.</p> Results <p>MR analysis identified 44 plasma proteins from the UKB-PPP database and 14 from the deCODE database significantly associated with AF/AFL, and only 3 proteins (NFKB1, PGD, PCSK9) were overlapped. Colocalization analysis further identified only PCSK9 (Proprotein convertase subtilisin/kexin type 9) shared a causative genetic variant with AF/AFL (PP.H4 &gt; 0.8). TWAS analysis also provided strong evidence to the association between PCSK9 and risks of AF/AFL. PheWAS have shown several potential side effects of PCSK9 inhibition (p_fdr &lt; 0.05). Moreover, MVMR analysis revealed that LDL-C, systolic/diastolic blood pressure, and inflammatory factors may exert partial mediation effects on the causal relationship between PCSK9 and AF/AFL.</p> Conclusion <p>This study identifies PCSK9 as a promising therapeutic target for AF/AFL, supported by consisitent evidence from MR, Bayesian colocalization, and TWAS analysis. And LDL-C, blood pressure, and inflammatory factors may exert partial mediation effects on the causal relationship between PCSK9 and AF/AFL.</p>