Osteoarthritis (OA) is a prevalent joint disease that can be exacerbated by lipid metabolism disorders. The intra-articular fat pad (IFP) has emerged as an active participant in the pathological changes of knee OA (KOA). However, the proteomic and lipidomic differences between IFP tissues from KOA and control individuals remain unclear. Samples of IFP were collected from individuals with and without OA (n = 6, n = 6). Subsequently, these samples underwent liquid chromatography/mass spectrometry-based label-free quantitative proteomic and lipidomic analysis to identify differentially expressed proteins (DEPs) and lipid metabolites (DELMs). The DEPs were further subjected to enrichment analysis, and hub DEPs were identified using multiple algorithms. Additionally, an OA diagnostic model was constructed based on the identified hub DEPs or DELMs. Furthermore, CIBERSORT was utilized to investigate the correlation between hub protein expression and immune-related modules in IFP of OA. Our results revealed the presence of 315 DEPs and eight DELMs in IFP of OA patients compared to the control group. Enrichment analysis of DEPs highlighted potential alterations in pathways related to coagulation, complement, fatty acid metabolism, and adipogenesis. The diagnostic model incorporating four hub DEPs (AUC = 0.861) or eight DELMs (AUC = 0.917) exhibited excellent clinical validity for diagnosing OA. Furthermore, the hub DEPs were found to be associated with immune dysfunction in IFP of OA. This study presents a distinct proteomic and lipidomic landscape of IFP between individuals with OA and those without. These findings provide valuable insights into the molecular changes associated with potential mechanisms underlying OA.