C-reactive protein (CRP) is an acute-phase protein and has been found to be a risk factor for acute kidney injury (AKI) and chronic kidney diseases (CKD). However, the role and mechanisms of CRP in AKI and CKD remain largely unclear. Clinically, elevated serum CRP is a risk factor or biomarker for patients with AKI and CKD. Interestingly, in critically ill COVID-19 patients, increased serum CRP is also associated with the development of AKI. Functionally, studies using human CRP transgenic mouse models find that CRP is pathogenic and can function as a mediator for AKI and CKD as mice overexpressing human CRP promote AKI and CKD. Mechanistically, CRP can promote AKI and CKD via NF-κB and Smad3-dependent mechanisms. We found that CRP can activate Smad3 signaling directly and cause AKI via the Smad3-p27-dependent G1 cell cycle arrest mechanism. Thus, targeting CRP-Smad3 signaling with a neutralizing antibody or Smad3 inhibitor can inhibit AKI. CRP acts not only as a biomarker but also as a mediator for AKI and CKD. CRP can activate Smad3 to induce cell death and cause progressive renal fibrosis. Thus, targeting CRP-Smad3 signaling may represent a promising therapy for AKI and CKD.