Frailty is common among individuals with chronic kidney disease (CKD), whereas its impact on incident CKD risk remains unknown. This study aimed to prospectively evaluate the association between frailty and incident CKD risk, exploring the potential modification role of genetic risk factors (GRS). A cohort of 275,442 UK Biobank participants (mean age 55.3 ± 8.1 years, 43.4% male) without CKD were included. Physical frailty was defined by Fried Frailty phenotypes (FP) and Rockwood Frailty Index (FI). New-onset CKD was identified through hospital inpatient records and death register. GRS for CKD were calculated based on 27 single-nucleotide variants. Cox proportional hazards models and Fine-Gray competing risk models were applied to evaluate the hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 14.1 years, 5771 incident CKD cases were documented. Cox models indicated that prefrailty and frailty were associated with an increased CKD risk, with HRs (95% CI) of 1.17 (1.10-1.24) and 1.74 (1.58-1.91) for FP, and 1.33 (1.24-1.41) and 1.87 (1.72-2.04) for FI. These associations remained significant after adjusting for competing risks. Estimated population attributable fractions of frailty for CKD were 5.6% (FP) and 9.9% (FI). A positive non-linear relationship between FI and CKD incidence was observed in women (P non-linearity < 0.001). Associations were strengthened in women and those under 60 years of age (P for interaction < 0.05). Frailty significantly interacted with genetic susceptibility (P for interaction < 0.001), with the highest CKD risk observed in participants with high genetic risk and frailty (HR, 95% CI; FI: 2.28, 1.90-2.74; FP: 1.88, 1.52-2.33). Pre-frailty and frailty associated with incident CKD, with further modulation by GRS. These findings have important implications of frailty assessment and management in CKD prevention.