Paracetamol may improve renal function in patients with severe Plasmodium knowlesi malaria, particularly in those with acute kidney injury and hemolysis, via inhibition of cell-free hemoglobin mediated oxidative kidney damage. We developed a population pharmacokinetic/pharmacodynamic (PK/PD) model to assess effects of paracetamol on creatinine, hepatotoxicity, fever clearance, and parasite clearance among Malaysian patients with predominantly non-severe knowlesi malaria using data from the PACKNOW trial (Clinical Trials Registration: NCT03056391). A total of 372 patients were included in the PK/PD analyses (paracetamol: n = 183, control: n = 189). Paracetamol PK was described using a prior PK model published in patients with falciparum malaria. The PK/PD demonstrated that higher paracetamol exposures were associated with a faster decline in both creatinine and fever clearance time, supporting its renoprotective and antipyretic effects. Increased paracetamol exposure was not associated with hepatotoxicity or serious adverse events, despite a weak positive association with liver transaminases over time. No significant relationship was observed between paracetamol exposure and parasite clearance. Overall, these findings highlight an exposure-response relationship for paracetamol and a decline in creatinine, supporting its use as a renoprotective drug in treating Plasmodium knowlesi malaria.