Background <p>Patients with chronic kidney disease (CKD) face an increased risk of atrial fibrillation (AF). Life’s Essential 8 (LE8)-based cardiovascular health (CVH) is associated with reduced cardiovascular risk. However, the relationship between LE8 and AF, and the mediating role of plasma proteins in CKD, remain unclear.</p> Methods <p>In 16,547 patients with CKD from the UK Biobank, LE8 scores were calculated from eight behavioral and biological metrics. Among 1,991 individuals with proteomic data, LE8 proteomic signatures were constructed using LASSO regression, which inherently handles multicollinearity through L1 regularization. Multivariable Cox models adjusted for relevant covariates were used to examine the associations of LE8 and proteomic signatures with incident AF. Mediation analyses were performed to identify proteins linking LE8 to AF.</p> Results <p>During a median follow-up of 13.1 years, 1,785 incident AF cases occurred. Compared with the lowest LE8 quartile (Q1), the hazard ratios (HRs) and 95% confidence intervals (CIs) for AF across Q2 to Q4 were 0.74 (0.66, 0.84), 0.60 (0.52, 0.68), and 0.60 (0.52, 0.69), respectively (<i>P</i>_trend &lt; 0.001). For the proteomic signature, the corresponding HRs were 0.86 (0.62, 1.19), 0.75 (0.54, 1.05), and 0.50 (0.33, 0.74) (<i>P</i>_trend = 0.001). LE8 scores showed a nonlinear inverse association with AF, whereas the proteomic signature exhibited a linear pattern. Mediation analyses identified 18 proteins (e.g., GDF15 and CLMP) that partially mediated the association between LE8 and AF.</p> Conclusions <p>Favorable LE8-based CVH and its proteomic signatures were significantly associated with lower AF risk among CKD patients. The identified proteomic mediators provide insights into biological pathways and potential molecular targets for AF prevention in CKD.</p>