Background: Topiramate (TPM) is a second-generation antiepileptic drug with a good pharmacokinetic profile; nonetheless, several factors such as age, renal function and concomitant medications have been reported to affect TPM clearance and dosage adjustments are necessary. Several population pharmacokinetic studies of TPM were developed and the results were partially inconsistent, with different predictors for TPM pharmacokinetic parameters and different structural models. Thus, we aimed to systematically summarise clinically significant covariates influencing TPM pharmacokinetics and clinical responses. Methods: PubMed, CINAHL Complete, Science Direct and SCOPUS databases were systematically searched from the date of their inception to May 2021. Studies conducted in humans employing a nonlinear mixed-effects approach were included in this review. Information from retrieved articles were independently extracted using the prespecified data abstraction form. Results: Ten studies were included and most of them characterised TPM pharmacokinetics with a linear one-compartment model. The estimated TPM clearance without covariate effects ranged from 1.15 to 2.25 L/h. Significant predictors for TPM clearance included concomitant medications, weight, age, creatinine clearance and TPM daily dose. Moreover, two studies reported the effect of TPM exposure on cognitive function, with limitations on the generalisability. Conclusions: Significant predictors for TPM clearance that are essential for individualising dosage regimens were concomitant medications, weight, age, creatinine clearance and TPM daily dose. High TPM levels had negative impacts on verbal fluency, working memory, attention and psychomotor speed; however, future studies with broader population characteristics are needed to increase generalisability.