Purpose <p>This study aimed to characterize the pharmacokinetics (PK) of meropenem in patients with renal impairment or on continuous renal replacement therapy (<i>CRRT</i>), investigate the factors contributing to PK variability, and evaluate the performance of different dosing regimens to optimize the pharmacokinetics/pharmacodynamics PK/PD) targets.</p> Methods <p>This study enrolled patients with severe infections and renal impairment who received meropenem treatment at the Second Affiliated Hospital of Soochow University. Participants were grouped according to whether <i>CRRT</i> was used. Meropenem concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC/MS–MS). A population pharmacokinetic (PPK) model for meropenem was developed using a nonlinear mixed-effects modeling (NONMEM) approach. Monte Carlo simulations were performed to evaluate the likelihood of achieving PK/PD targets and the risk of adverse events across various dosing regimens.</p> Results <p>A total of 54 patients were included in the study. A two-compartment model was used as a structural model and <i>CRRT</i> was identified as a significant covariate of clearance (<i>CL</i>). The estimated typical value of <i>CL</i> was 2.47 L/h. Under physiological conditions, renal impairment usually leads to a decrease in meropenem clearance. Compared with patients with renal impairment (estimated glomerular filtration rate &lt; 45 mL/min/1.73 m²), <i>CRRT</i> can increase meropenem clearance by 2.1 times. Monte Carlo simulations suggested that for patients undergoing <i>CRRT</i>, the administration regimen of 0.5 g q6h (3 h infusion) is recommended; whereas for non-<i>CRRT</i> patients with renal impairment, the regimen of 0.5 g q8h (1 h infusion) was advised.</p> Conclusions <p>The study identified that <i>CRRT</i> significantly affected the exposure of meropenem in patients with renal impairment. Therefore, individualized medication for <i>CRRT</i> patients is of great importance.</p>