An investigation employing the semiempirical molecular orbital MNDO method in the program package of the HyperChem 7.5 software to calculate ΔH_f(M), ΔH_f [M+H]⁺ and local proton affinities (PAs) as well as the charge distributions for the two highly electronegative hetero atoms (O₁₁ and N₁) in six quinolone derivatives have been undertaken. The MNDO calculated values of PAs for the quinolone derivatives at site O₁₁ and at site N₁ indicate that the average energy separation between PA values at two respective sites is equal to about 164 kJ.mol^-1. This allows the authors to conclude that the protonation at site O₁₁ is a more favoured process than at N₁. This conclusion can be explained as resulting from the presence of unsaturated carbonyl (C ═ O) double bond and ion pair electrons of the oxygen atom, which increase the influences of the protonation at O₁₁ site, which is known to be a good proton acceptor. The preferential protonation at site O₁₁ for the studied molecules have been confirmed by the calculated ΔH_f [M+H]⁺ values at sites O₁₁ and N_1.