Temporomandibular joint osteoarthritis (TMJOA) is a common group of clinical diseases and is an important subtype of temporomandibular joint disorder (TMD). Increased intrajoint pressure or weakened penetration can exacerbate the hypoxic state of the condylar cartilage microenvironment. In this study, TMT labeling quantitative proteomic technology was used to comprehensively explore the impacts of and pathways affected by LIPUS on the biological functions of chondrocytes under hypoxic conditions. Bioinformatic analysis revealed differentially expressed proteins (DEPs) in the N group versus the L group and the L group versus the LP group. Considering the results of gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analyses, we hypothesized that LIPUS can activate the FAK signaling pathway. This study identified a new molecular marker to determine the efficacy of LIPUS in TMJOA, providing a theoretical basis for the clinical application of LIPUS in the treatment of TMJOA.