A simple chiral electrochemical sensor based on hydroxypropyl chitosan (HPCS) covalently bound to multi-walled carbon nanotubes (MWCNTs) was developed for the recognition of mandelic acid (MA) enantiomers. HPCS preferably combines with (S)-MA over (R)-MA, which was attributed to the favorable host–guest interactions between HPCS and the MA enantiomers. In addition, the recognition efficiency was significantly increased after hydroxypropyl groups were grafted onto chitosan (CS), which may be due to a stereo-hindrance effect. Moreover, the electrochemical recognition of amino acid enantiomers was investigated; the functional groups of the enantiomers play an important role in the enantioselective discrimination.