The problem of the bioavailability of water-soluble drugs can be staggering in formulation when the drug dissolves readily in body fluids. Electrostatic spraying, a sophisticated particle engineering technology, has been identified as one of the most potential methods of managing the size of these drugs to improve their bioavailability. In this review, the author discusses the principles and mechanisms that are fundamental to electrostatic spraying and, more importantly, the possibility of adjusting the dimensions of particles that are so important for drug dissolution, drug absorption, and drug bioavailability. Due to the nanoscale processing of water-soluble drugs, it is achievable to extend their time in the small intestine, increase their absorption by biological membranes, and maintain stable release characteristics. This article will critically discuss the parameters affecting particle formation during electrostatic spraying, solvents used, spray parameters, environmental parameters, etc. Examples of case studies and experimental works that validate the use of the electrostatic spray technique for bioavailability improvement will be presented. The possible limitations of the structure, issues in scaling up, and the prospects of refining the technique in the future will also be discussed. The present analysis aims to offer a comprehensive understanding of electrostatic spraying for achieving bioavailability barriers in water-soluble drugs and to advance the domains of drug delivery systems.