The oral route remains the preferred modality for chronic drug administration due to patient convenience and compliance; however, approximately 40% of approved drugs and 70% of new chemical entities exhibit poor aqueous solubility that limits gastrointestinal absorption and therapeutic efficacy. The Biopharmaceutics Classification System categorizes these compounds as Class II (low solubility, high permeability) and Class IV (low solubility, low permeability), presenting distinct formulation challenges requiring mechanistically designed delivery systems. This review examines contemporary biopharmaceutical strategies for enhancing oral bioavailability through solubility and dissolution rate improvement, with emphasis on the physicochemical principles governing each approach. Solid dispersions utilizing hydrophilic polymers achieve thermodynamic stabilization of amorphous drug forms, generating supersaturated solutions that drive absorption. Nanocrystal technologies exploit surface area-to-volume relationships through particle size reduction, enabling dissolution rates that overcome gastrointestinal transit limitations. Lipid-based formulations—including self-emulsifying drug delivery systems, nanoemulsions, and lipid nanoparticles—facilitate drug solubilization within the gastrointestinal milieu and exploit lymphatic transport pathways to bypass hepatic first-pass metabolism. Polymeric and lipid nanocarriers provide encapsulation matrices that control drug release while protecting against enzymatic degradation. Hybrid platforms incorporating mesoporous silica or cyclodextrin complexes combine multiple enhancement mechanisms for synergistic bioavailability improvement. In vitro–in vivo correlation utilizing bio relevant dissolution media enables predictive formulation development and regulatory acceptance. Comparative evaluation reveals trade-offs among stability, manufacturability, and enhancement magnitude that guide technology selection based on drug physicochemical properties and therapeutic requirements. Challenges including supersaturating maintenance, polymorphic transformation, and patient variability necessitate continued innovation toward personalized oral delivery systems integrating artificial intelligence-driven formulation design.