Background/Objectives: Drugs exhibiting poor aqueous solubility present a challenge to efficient delivery to the site of action. Spanlastics (a nano, surfactant-based drug delivery system) have emerged as a powerful tool to improve solubility, bioavailability, and delivery to the site of action. This study aimed to better understand factors affecting the physicochemical properties of spanlastics, quantify their effects, and use them to enhance the bioavailability of famotidine (FMT), a model histamine H2 receptor antagonist (BCS class IV). Methods: FMT was incorporated into nano-spanlastics drug delivery system. The ethanol injection method, Box–Behnken design, and mathematical modeling were utilized to fabricate famotidine-loaded nano-spanlastics and optimize the formula. Spanlastics were characterized for their particle size, polydispersity index, zeta potential, entrapment efficiency, drug loading, compatibility of the excipients (using DSC), in vitro drug release, and in vivo pharmacokinetics. Results: Span 60 (the non-ionic surfactant) and tween 60 (the edge activator) gave rise to spanlastics with the best characteristics. The optimal spanlastic formulation exhibited small particle size (<200 nm), appropriate polydispersity index (−30 mV). The entrapment efficiency and drug loading of the optimum formula assured its suitability for hydrophobic drug entrapment as well as practicability for use. DSC assured the compatibility of all formulation components. The drug release manifested a biphasic release pattern, resulting in a fast onset and sustained effect. Spanlastics also showed enhanced C_max, AUC_0–24, and bioavailability. Conclusions: Spanlastics manifested improved FMT dissolution, drug release characteristics, membrane permeation, and pharmacokinetic behavior.