Antibody-drug conjugates (ADCs) are complex biotherapeutics comprising a monoclonal antibody, a linker, and a cytotoxic payload. Their stability is influenced by both antibody degradation pathways and linker-payload physicochemical properties, making forced degradation studies essential for developing stability-indicating methods. In this study, three approved ADC products—Adcetris® (brentuximab vedotin), Trodelvy® (sacituzumab govitecan), and Enhertu® (trastuzumab deruxtecan)—were comparatively evaluated using size-exclusion chromatography (SEC), hydrophobic interaction chromatography (HIC), and ion-exchange chromatography (IEX) under thermal, oxidative, hydrolytic, freeze–thaw, and photostress conditions. Adcetris® was predominantly prone to aggregation, with increased high-molecular-weight species under acidic hydrolysis and oxidative stress. Trodelvy® showed the most pronounced chromatographic changes, including extensive HIC peak redistribution under hydrolytic stress and significant IEX main peak loss under oxidative stress. Enhertu® remained relatively stable under freeze–thaw and thermal stress but showed pH-dependent instability under hydrolytic stress. Overall, combining SEC, HIC, and IEX provided complementary analytical fingerprints for evaluating stress-specific degradation liabilities and offered insights into quality assessment and stability-indicating strategy development for ADCs.