Background: Delafloxacin (DFX) is a broad spectrum quinolone with activity against methicillin-resistant Staphylococcus aureus being developed for the treatment of acute bacterial skin and skin-structure infections. A population PK (PPK) model was developed and covariate exploration was conducted for DFX using Phase 1 and 2 data. Methods: Data were obtained from 8 studies: 4 (3 Phase 1, 1 Phase 2) used IV formulations and 4 (Phase 1) used PO formulations. A wide range of DFX doses were administered (50 to 1200 mg as single or multiple doses); no subjects received both IV and PO doses. PPK analyses were conducted using Monte-Carlo parametric expectation maximization (SADAPT 1.5.6). A PPK model for IV data was fit first followed by inclusion of the PO data. After the best PPK model was identified, covariate exploration was conducted on DFX AUC0-24,ss (for a maintenance regimen of 300 mg/day) using statistical models. Results: The PPK dataset contained 9,716 plasma concentrations from 258 subjects. The final PPK model was a 2-compartment model with first-order absorption or zero-order infusion and parallel linear and nonlinear elimination. PPK parameters were assumed to be log-normally distributed; error variance models were additive plus proportional (separate models for IV and PO data). Core PPK parameter estimates were estimated with excellent precision (%SEM values of 2 to 6%); %CV in clearance parameters was moderate (30 to 60%); goodness-of-fit diagnostics indicated an unbiased fit to the data and an r2 of 0.944 for observed vs individual fitted concentrations. Median (range) AUC0-24,ss was 22 (7.5 54) mg/L·h. Other than the route of administration (~15% lower exposure with PO), the only significant predictor of DFX AUC0-24,ss was body weight; average AUC0-24,ss decreased by ~40% over the weight range of 50 to 105 kg. Conclusions: This PPK model for DFX, which fit the data well, has served as the basis for developing sparse PK sampling schemes and guiding dose selection for future clinical trials.