Osteophyte is one of the inevitable consequences of progressive osteoarthritis with the main characteristics of cartilage degeneration and endochondral ossification. The pathogenesis of osteophyte formation is not fully understood to date. In this work, metabolomic approaches were employed to explore potential mechanisms of osteophyte formation :by detecting metabolic variations between extracts of osteophyte cartilage tissues (n = 32) and uninvolved control cartilage tissues (it = 34), based on the platform of ultraperformance liquid chromatography tandem quadrupole time-of-flight mass spectrometry, as well as the use of multivariate statistic. analysis and univariate statistic analysis. The osteophyte group was-significantly separated from the control group by the orthogonal partial least-squares discriminant analysis models, indicating that metabolic state of osteophyte cartilage had been changed. In total, 28 metabolic:variations further validated by mass spectrum (MS) match, tandom mass spectrum (MS/MS) match, and standards match Mainly included amino acids, Ramie acids, glycerophospholipids, and fatty acyls. These metabolites were related to some specific physiological or pathological processes (collagen dissolution, boundary layers destroyed, self-restoration triggered, etc.) which might be associated with the procedure of osteophyte formation. Pathway analysis showed phenyialanine metabolism (PI = 0.168, p = 0.004) was highly correlative to this degenerative process. Our findings provided a direction for targeted metabolomic study and an insight into further reveal the molecular mechanisms of ostophyte formation.