Over several decades, poly (lactic-co-glycolic acid) (PLGA) have been widely used as Micro-and Nano-carriers of therapeutic agents for drug delivery applications. However, encapsulation process of therapeutic agents into PLGA Nanoparticles (NPs) necessitates a defined step to understand the effects and interactions of parameters involved in production process. In pharmaceutics formulations, compared to one factor at a time (OFAT) approach, statistical design of experiments (DOE) supersedes OFAT approach due to limited number of experiments required to investigate effects and interactions of a process parameters. The major objectives of the present study were to: 1) prepare and understand the effect of selected formulation parameters on particles size and drug recovery of PLGA NPs encapsulating Ciprofloxacin Hydrochloride (Cip-HCl) using a fractional factorial design (FFD) as a DOE approach; 2) understand the in-vitro release of Cip-HCl from PLGA NPs. Cip-HCl loaded PLGA were prepared by W₁/O/W₂ double emulsion solvent evaporation (DESE) method using poly-vinyl alcohol as a stabilizer. The Sizes of NPs were within 202 nm to 530 nm and percentage Cip-HCl recovered from dried NPs were within 1.7% w/w to 15.7% w/w. Increasing concentrations of PLGA and Cip-HCl was observed to increase NPs size. Increasing PVA concentration was observed to either reduce or increase NPs size. Increasing PLGA concentration was observed to increase the amount of Cip-HCl recovered. Within 1-24 hours, optimized formulations shows a controlled release of Cip-HCl from PLGA NPs.