Purpose <p>To evaluate the safety of creatine supplementation on kidney health in healthy individuals and patients with CKD.</p> Methods <p>The MEDLINE, Embase, Cochrane Library, and Google Scholar databases were systematically searched for RCTs from inception to March 2025. Studies comparing creatine supplementation with placebo in human subjects that assessed kidney health parameters were selected by 2 independent reviewers following PRISMA guidelines. A random-effects model was used to pool mean differences with 95% CI. The primary outcome was serum creatinine level. Secondary outcomes included GFR assessed by creatinine-based methods and by Cr-EDTA, serum urea, albuminuria, proteinuria, and urinary creatinine.</p> Results <p>Twenty-six studies (1036 participants) were included. Creatine supplementation was associated with a significant increase in serum creatinine levels (MD, 0.14&#xa0;mg/dL; 95% CI 0.05–0.22; <i>P</i> = .002; <i>I</i>² = 93.9%) and a reduction in GFR assessed by creatinine-based methods (MD, –10.75&#xa0;mL/min; 95% CI –17.48 to –4.02; <i>P</i> = .002; <i>I</i>² = 0%). No significant differences were observed when assessed by Cr-EDTA (MD, 5.89&#xa0;mL/min; 95% CI –0.30 to 12.08; <i>P</i> = .06; <i>I</i>² = 6.3%) or in serum urea, albuminuria, proteinuria, and urinary creatinine. In the hemodialysis subgroup, creatine supplementation was associated with a significant increase in serum creatinine; conversely, serum urea levels were significantly reduced.</p> Conclusions <p>Creatine supplementation is associated with increased serum creatinine levels and reduced glomerular filtration rate estimated by creatinine-based methods in healthy individuals and patients with chronic kidney disease. These findings likely reflect altered creatinine metabolism rather than kidney injury, given the absence of changes when assessed using Cr-EDTA.</p> Trail registry <p>CRD420251015042.</p>