Background/Objectives : Initially approved for the treatment of major depressive disorder, doxepin’s clinical applications have expanded to include pruritus and insomnia due to its receptor-specific activities at varying doses. This narrative review highlights the pharmacokinetics of doxepin, emphasizing its metabolism via CYP2D6 and CYP2C19 enzymes and the clinical implication of enzyme inhibition or induction. Methods: A literature search was performed using databases including PubMed, Embase, and Google Scholar, with no restrictions on publication date Results: Doxepin is primarily metabolized by CYP2D6 and CYP2C19, with inhibitors like fluoxetine, sertraline, cimetidine, and fluvoxamine increasing its plasma levels. Pharmacogenomic variations in CYP2D6 and CYP2C19 can also impact metabolism Conclusions Findings from this review suggest that while high-dose doxepin therapy may present notable interaction risks, low doses for insomnia are generally well-tolerated with minimal clinical consequences.