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CPX‐351, a dual‐drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, is approved in the United States for adults with newly diagnosed therapy‐related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia‐related changes. Population pharmacokinetics analyses were performed using nonlinear mixed‐effect modeling on pooled data from 3 clinical studies, and the impact of CPX‐351 exposures on efficacy and safety was assessed. The pharmacokinetics of cytarabine and daunorubicin were described using 2‐compartment models with linear elimination. None of the evaluated covariates had a clinically significant impact on plasma exposure to total cytarabine or daunorubicin, while bilirubin and formulation showed statistically significant effects on pharmacokinetic parameters of cytarabine and daunorubicin, respectively. In patients with mild/moderate renal impairment or serum bilirubin ≤3 mg/dL, plasma exposures to cytarabine and daunorubicin following CPX‐351 were within the variability range for patients with normal kidney function or serum bilirubin levels. Exposure‐response analysis demonstrated that better efficacy outcomes were associated with higher CPX‐351 exposure quartiles. Early mortality rates in all CPX‐351 exposure quartiles were lower vs the 7 + 3 control group, and lower mortality rates were associated with higher exposure quartiles. A trend toward greater frequency of grade 3 treatment‐emergent adverse events (but not grade 4/5 events) was observed at higher CPX‐351 exposure quartiles. Overall, the population pharmacokinetic analyses indicate no adjustments to the recommended dose and schedule of CPX‐351 are warranted for patients with mild/moderate renal impairment or serum bilirubin ≤3 mg/dL. Results from the exposure‐response analyses suggest the current CPX‐351 regimen provides a favorable risk‐benefit profile. [ABSTRACT FROM AUTHOR]