The infrapatellar fat pad (IFP) is involved in the occurrence and progression of osteoarthritis (OA), yet the proteomic changes in the IFP during OA are not well understood. In this study, we selected the IFP from patients undergoing late-stage total knee arthroplasty as the experimental group, while the IFP from patients undergoing repair surgery for acute anterior cruciate ligament rupture served as the control group. Using label-free protein quantification technology, we analyzed the protein expression levels in the experimental and control groups. We identified 315 differentially expressed proteins that are primarily associated with functions such as coagulation, complement, fatty acid metabolism, and adipogenesis. These findings shed light on the potential molecular mechanisms underlying the involvement of the IFP in OA pathogenesis.