CYP2C9 substrates can exhibit both hyperbolic and atypical kinetic profiles, and their metabolism can be activated or inhibited depending on the effector studied. CYP2C9 genetic variants can also affect both substrate turnover and kinetic profile. The present study assessed whether analogs of the effector amiodarone differentially altered the atypical kinetic profile of the substrate naproxen and whether this effect was genotype-dependent. Amiodarone, desethylamiodarone, benzbromarone, and its dimethyl analog (benz(meth)arone) were incubated with naproxen and either CYP2C9.1 or CYP2C9.3. Amiodarone activated naproxen demethylation at lower concentrations, regardless of the CYP2C9 allele, and inhibited metabolism at higher concentrations without altering the kinetic profile. Desethylamiodarone was a potent inhibitor of naproxen demethylation, irrespective of the CYP2C9 allele. Benzbromarone altered naproxen demethylation kinetics from a biphasic profile to that of a hyperbolic form in CYP2C9.1 and CYP2C9.3, resulting in inhibition and activation, respectively. In contrast, benz(meth)arone activated naproxen demethylation in both CYP2C9.1 and CYP2C9.3. In addition, the kinetic profile of naproxen demethylation became more hyperbolic at lower concentrations of benz(meth)arone and then reverted back to biphasic as the benz(meth)arone was increased further. Equilibrium binding and multiple-ligand docking studies were used to propose how such similar compounds exerted very different effects on naproxen metabolism. In summary, effectors of CYP2C9 metabolism can alter not only the degree of substrate turnover (activation or inhibition) but also the kinetic profile of metabolism of CYP2C9 substrates through effects on substrate binding and orientation. In addition, these kinetics effects are concentration- and genotype-dependent.