The paradigm of pharmaceutical analysis is undergoing a critical transition from traditional empirical Quality by Testing (QbT) frameworks to systematic, risk-based methodologies encapsulated by the Analytical Quality by Design (AQbD) initiative. This shift is particularly crucial for Fixed-Dose Combinations (FDCs), where the simultaneous estimation of multiple active pharmaceutical ingredients (APIs) presents complex chromatographic challenges. This review aims to critically evaluate the application of AQbD principles in the development, optimization, and validation of High-Performance Liquid Chromatography (HPLC) methods for multi-component pharmaceutical formulations. AQbD facilitates the establishment of a Method Operable Design Region (MODR) through rigorous risk assessment tools (Ishikawa diagrams, Failure Mode and Effects Analysis) and sophisticated Design of Experiments (DoE) modeling (e.g., Box-Behnken and Central Composite designs). The integration of AQbD ensures optimal Critical Analytical Attributes (CAAs), such as resolution and peak symmetry, by systematically controlling Critical Method Parameters (CMPs). Furthermore, the coupling of AQbD with Green Analytical Chemistry (GAC) metrics promotes eco-friendly analytical lifecycles. The implementation of AQbD provides unprecedented regulatory flexibility, superior method robustness, and enhanced sustainability. It is rapidly becoming the mandatory gold standard for securing the quality, safety, and efficacy of complex fixed-dose therapeutic regimens.