Calcific aortic valve disease (CAVD) is the most common valvular heart disease in older adults, but no medical therapy is currently able to halt or reverse its progression, partly because the molecular mechanisms of valve remodeling remain incompletely understood. Here, we aimed to dissect the extracellular matrix (ECM)-centered mechanisms altered in CAVD by integrating untargeted and targeted proteomics, degradomics, collagen post-translational modification (PTM) mapping, and histology in human aortic valves. We analyzed valvular tissue from patients with severe aortic stenosis (n = 10) and non-stenotic controls (n = 9) using data-independent acquisition (DIA) LC–MS/MS, followed by Gene Ontology enrichment, semi-tryptic peptide profiling, hydroxyproline-focused PTM analysis, Multiple Reaction Monitoring (MRM) validation, and elastin staining. DIA proteomics quantified 1,971 proteins and identified 462 significantly modulated in severe CAVD, revealing a landscape dominated by complement activation, coagulation and fibrinolysis, humoral immune response, and extensive ECM organization and wound-healing programs, alongside down-regulation of biosynthetic and metabolic pathways. A degradomic-like analysis of 1,564 semi-tryptic peptides, filtered to exclude proteins with overall abundance changes, yielded 11 preferential ECM substrates, forming a highly interconnected network enriched in small leucine-rich proteoglycans (decorin, lumican, PRELP), microfibrillar components (fibrillin-1), and collagen VI, with fibrinogen and complement C1s bridging toward the thrombo-inflammatory milieu. Collagen-specific PTM mapping demonstrated a marked increase in hydroxyproline-containing peptides in several fibrillar and non-fibrillar collagen chains, despite largely unchanged or even reduced total collagen abundance, indicating qualitative remodeling with enhanced collagen maturation and potential ECM stiffening rather than simple protein accumulation. Histological assessment using Verhoeff–Van Gieson staining confirmed prominent elastin rarefaction and fragmentation with collagen-rich replacement in stenotic cusps. MRM validation of a focused panel of coagulation, complement, and ECM-related proteins (including F2, F9, F10, C3, KNG1, FGG, KLKB1, ACAN, EMILIN1, and HTRA1) corroborated their up-regulation in diseased valves. Together, these multi-layer data support a model in which CAVD is driven by an ECM-centered, thrombo-inflammatory remodeling process characterized by selective proteolysis of key structural matrix components, collagen PTM dysregulation, and loss of elastin integrity. This integrated “structural–degradomic–PTM” signature may provide a basis for developing tissue and circulating biomarkers of disease activity and for identifying novel targets to modulate matrix remodeling in calcific aortic valve disease.