In this study, we examined how interactions between solvent molecules and various sites on gatifloxacin (GFX) affect the stability and photoexcitation of the system. The ground- and excited-state properties of protonated and deprotonated GFX surrounded by (up to) six explicitly included water molecules (GFX\(\cdots\)6H\(_{2}\)O) were calculated using density functional theory (DFT) and time-dependent DFT (TD-DFT), employing two exchange-correlation functionals (CAM-B3LYP and M06-2X) and three basis sets: 6-311++G(d,p), aug-cc-pVTZ, and def2-TZVP. Implicit solvation effects were modeled with the polarizable continuum model (PCM). Comparison with recent results for isolated GFX indicated that hydrogen bonding with water molecules plays a crucial role in stabilizing the deprotonated form of GFX and in modulating the photoexcitation of the protonated species. For example, at the CAM-B3LYP/def2-TZVP level in water, a red shift of \(\approx\) -0.07 eV was observed in the first open singlet excited state of GFX\(\cdots\)6H\(_{2}\)O relative to the corresponding result obtained for GFX with only implicit solvation. This shift is likely due to hydrogen bonding interactions within GFX\(\cdots\)6H\(_{2}\)O.