The 2017 FDA safety review regarding the CNS (central nervous system) side effects associated withthe systemic use of fluoroquinolones antibacterials (FQs) was the key motivation to carry out this work.The main objective of this study is to investigate lipophilicity and retention parameters of some selectedfluoroquinolones antibacterials (FQs) namely; levofloxacin (LEV), ofloxacin (OFL), gatifloxacin (GAT), nor-floxacin (NOR), sparfloxacin (SPA), ciprofloxacin (CIP) and lomefloxacin (LOM) using salting-out thinlayer chromatography (SOTLC). Statistically significant correlations between the chromatographically-obtained retention parameters and experimental log P values were found and expressed as quantitativestructure retention relationship (QSRR) equations. Principal component analysis was carried out toexplain the variation between chromatographic and both experimental and computed lipophilicityparameters. In another aspect of this study, a comparison between the chromatographically-determinedretention parameters (for five of the drugs under study) obtained using SOTLC (current study) and rel-ative lipophilicity (RM0) determined using a previously reported RP (reversed-phase)-TLC method wascarried out. Statistically significant correlation between the two methods was found, although RM0valuesobtained using SOTLC was lower than those reported using RP-TLC. Multiple linear regression analysiswas performed to predict MIC (minimum inhibitory concentration) and blood brain barrier (BBB) pene-tration of the examined drugs in which efficient QSAR (quantitative structure-activity relationship) andQSPR (quantitative structure-property relationship) models were generated using the calculated chro-matographic parameters (RM0and C0). The described models can provide a useful approach to predict MICand BBB penetration of newly synthesized FQs targeting to increase their activity against Gram-positiveorganisms and to minimize the associated CNS side effects.