Stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) methods are indispensable in pharmaceutical development, regulatory submissions, and quality control. These methods ensure accurate quantification of active pharmaceutical ingredients (APIs) in the presence of degradation products, process impurities, and formulation excipients. Recent years (2020–2025) have witnessed considerable advancements in chromatographic selectivity optimization, forced degradation design, impurity profiling, analytical Quality by Design (AQbD), and environmentally sustainable analytical practices. This review critically evaluates contemporary strategies in stability-indicating RP-HPLC method development, validation under ICH Q2 (R1/R2), degradation pathway assessment, regulatory expectations, and emerging trends including lifecycle management and green analytical chemistry. Emphasis is placed on practical implementation challenges and industry-oriented best practices.