Background and aims: Oxidative stress (OS) induces the production of fibroblast growth factor 21 (FGF21). Previous data have revealed that FGF21 protects cells from OS injury and death, making it a potential therapeutic option for many diseases with increased OS. However, the association of this growth factor with OS markers in humans with chronic kidney disease (CKD) remains unknown. This study aims to evaluate the association of serum FGF21 with serum total antioxidant capacity (TAC) and oxidized low-density lipoproteins (OxLDL) in subjects in different stages of kidney disease. Methods: This is a cross-sectional study that included 382 subjects with different stages of CKD, irrespective of type 2 diabetes (T2D) diagnosis. Associations of serum FGF21 with OxLDL, TAC, sex, age, body mass index (BMI), fasting plasma glucose, estimated glomerular filtration rate (eGFR), T2D, and smoking, were evaluated through bivariate and partial correlation analyses. Independent associations of these variables with serum FGF21 were evaluated using multiple linear regression analysis. Results: Serum FGF21 was significantly and positively correlated with age ( r = 0.236), TAC (lnTAC) ( r = 0.217), and negatively correlated with eGFR ( r = −0.429) and male sex ( r = −0.102). After controlling by age, sex, BMI, T2D, smoking, and eGFR; both TAC and OxLDL were positively correlated with FGF21 ( r = 0.117 and 0.158 respectively, p < 0.05). Using multiple linear regression analysis, eGFR, male sex, T2D, OxLDL, and TAC were independently associated with serum FGF21 (STDβ = −0.475, 0.162, −0.153, 0.142 and 0.136 respectively; p < 0.05 for all) adjusted for age, BMI, smoking, and fasting plasma glucose. Conclusion: A positive association between serum FGF21 and OS has been found independently of renal function in humans. Results from the present study provide novel information for deeper understanding of the role of FGF21 in OS in humans with CKD and T2D; mechanistic studies to explain the association of serum FGF21 with oxidative stress in CKD are needed.