Objectives: Fibroblast growth factor 21 (FGF21) plays a critical role in glucose, lipid, and energy metabolism. However, the relationship between FGF21 and the risk of chronic kidney disease (CKD) has not yet been explored. Methods: We analyzed 17,107 participants without CKD from UK biobank cohort who measured baseline plasma FGF21 levels using proximity extension assay. The primary outcome was a composite CKD outcome, defined as the development of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 or urine albumin-creatinine ratio (uACR) >30 mg/g on at least two occasions 90 days apart. The secondary outcomes were individual occurrences of eGFR-based CKD and the development of albuminuria. Results: Participants with higher FGF21 levels were older and more likely to be male, smokers, and obese. They exhibited more comorbidities and concomitant medication use, and less favorable metabolic and lipid profiles. During 127,832 person-years of follow-up, the composite outcome occurred in 853 (5.0%) participants. The incidence of CKD increased progressively in participants with higher FGF21 levels (2.7%, 4.4%, 5.0%, and 7.8% from Q1 to Q4, respectively; P-for-trend <0.001). In Cox regression analysis, compared with Q1, the adjusted hazard ratios (aHRs) (95% CIs) for composite CKD outcome were 1.41 (1.11-1.79), 1.65 (1.30-2.09), and 2.07 (1.65-2.60) for Q2, Q3, and Q4, respectively (P-for-trend <0.001). Similar results were observed in secondary analysis for the occurrence of eGFR < 60 mL/min/1.73 m2 (aHR [95% CI]; Q2, 1.46 [1.13-1.88]; Q3, 1.69 [1.32-2.17]; Q4, 2.03 [1.59-2.58] versus Q1; P-for-trend <0.001) and the development of albuminuria (aHR [95% CI]; Q2, 1.10 [0.57-2.14]; Q3, 1.62 [0.88-2.99]; Q4, 2.49 [1.40-4.42] versus Q1; P-for-trend <0.001). Conclusions: Higher FGF21 levels were associated with an increased risk of incident CKD in UK adults, suggesting that FGF21 may serve as a potential biomarker for predicting the development of CKD.