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Anxiety disorders in the pediatric population represent a highly prevalent mental health concern whose pharmacological management has been consolidated through the use of selective serotonin reuptake inhibitors (SSRIs). Among these agents, sertraline is one of the most frequently prescribed; however, its efficacy and safety in children and adolescents exhibit substantial interindividual variability, largely attributed to clinical, physiological, and genetic factors. This review aimed to analyze the current evidence on the efficacy, safety, and optimization strategies for sertraline therapy in pediatric patients, with a particular focus on pharmacokinetic and pharmacogenetic determinants that modulate therapeutic response. Available evidence indicates that genetic variants in CYP2C19, CYP2D6, and ABCB1 significantly influence hepatic metabolism, plasma exposure, and drug tolerability. These differences support the integration of pharmacogenetic testing as a clinical tool to individualize dosing and prevent adverse effects. In addition, population pharmacokinetic modeling has emerged as a valuable approach to design personalized therapeutic regimens, especially for patients with medical comorbidities or atypical metabolic profiles. In conclusion, the integration of clinical, genetic, and pharmacokinetic information into pediatric psychiatric practice may facilitate the advancement of precision medicine, promoting safer, more effective, and individualized sertraline-based treatments for anxiety disorders in children and adolescents.