Poor aqueous solubility is a major limitation in pharmaceutical development, affecting nearly 40% of approved drugs and up to 90% of drug candidates in the discovery pipeline. Low solubility directly compromises oral bioavailability, therapeutic effectiveness, dose proportionality, and clinical reproducibility, particularly for drugs classified under Biopharmaceutical Classification System (BCS) Classes II and IV. To address these challenges, formulation science has advanced significantly over the past two decades. This review critically evaluates recent progress from 2022 to 2025 in three major technological approaches: solid dispersions, lipid-based formulations, and nanotechnology-enabled drug delivery systems. Emphasis is placed on mechanistic principles governing solubility enhancement, formulation design strategies, in vivo performance outcomes, and translational considerations. Emerging hybrid platforms that integrate polymers, lipids, and nanocarriers are also discussed, as they demonstrate synergistic improvements in dissolution rate, permeability, and systemic exposure, often achieving 3–7 fold enhancement in oral bioavailability. In addition, the evolving regulatory landscape for complex and nanotechnology-based formulations is examined, highlighting current expectations for characterization, stability, and safety evaluation. Overall, this review provides an updated and integrated perspective on formulation strategies for poorly soluble drugs, offering practical insights for both academic research and industrial development.