Background/Objectives: Quality by Design (QbD) has revolutionized pharmaceutical development by transitioning from reactive quality testing to proactive, science-driven methodologies. Rooted in ICH Q8–Q11 guidelines, QbD emphasizes defining Critical Quality Attributes (CQAs), establishing design spaces, and integrating risk management to enhance product robustness and regulatory flexibility. This review critically examines QbD’s theoretical frameworks, implementation workflows, and industrial applications, aiming to bridge academic research and commercial practices while addressing emerging challenges in biologics, advanced therapies, and personalized medicine. Methods: The review synthesizes regulatory guidelines, case studies, and multidisciplinary tools, including Design of Experiments (DoE), Failure Mode Effects Analysis (FMEA), Process Analytical Technology (PAT), and multivariate modeling. It evaluates QbD workflows—from Quality Target Product Profile (QTPP) definition to control strategies—and explores advanced technologies like AI-driven predictive modeling, digital twins, and continuous manufacturing. Results: QbD implementation reduces batch failures by 40%, optimizes dissolution profiles, and enhances process robustness through real-time monitoring (PAT) and adaptive control. However, technical barriers, such as nonlinear parameter interactions in complex systems, and regulatory disparities between agencies hinder broader adoption. Conclusions: QbD significantly advances pharmaceutical quality and efficiency, yet requires harmonized regulatory standards, lifecycle validation protocols, and cultural shifts toward interdisciplinary collaboration. Emerging trends, including AI-integrated design space exploration and 3D-printed personalized medicines, promise to address scalability and patient-centric needs. By fostering innovation and compliance, QbD remains pivotal in achieving sustainable, patient-focused drug development.