A set of accessible chiral selectors containing vancomycin as a glycopeptide antibiotic, tryptophan as an amino acid and 2-hydroxypropyl-β-cyclodextrin (Hp-β-CD) was tested against naproxen as a chiral acidic pharmaceutical compound for enantiomeric separation in capillary electrophoresis to investigate their effectiveness and compare their functions. The experience performed under the optimum conditions shows that among three chiral additives employed, vancomycin is the most effective chiral selector for the enantioseparation of naproxen. In addition, a deeper insight into the enantioseparation mechanism was gained by thermodynamic characterization. The obtained thermodynamic parameters indicate that enantioseparation using the Hp-β-CD chiral selector is enthalpy driven, while separation by vancomycin is entropy and enthalpy driven. Also, chiral discrimination behavior of naproxen in vancomycin-mediated CE is mostly governed by the electrostatic interactions, while inclusion complexation between Hp-β-CD and naproxen plays a crucial role in enantioseparation using cyclodextrin. The calibration curves showed good linearity using vancomycin and Hp-β-CD chiral selectors. The quantification limits values of 1.0 and 0.5 µg/mL were obtained for vancomycin and Hp-β-CD-based methods, respectively.