Articular conditions are common in horses and can result in loss of function, chronic pain and/or inability to work. Common conditions include osteoarthritis, osteochondrosis and synovial sepsis, which can be life-threatening, but despite the high clinical prevalence of these conditions, rapid and specific diagnosis, monitoring and prognostication remains a challenge for practicing veterinarians. Synovial fluid from a range of arthropathies was enriched for low abundance proteins using combinatorial peptide ligand ProteoMiner™ beads and analysed via liquid chromatography-tandem mass spectrometry. Changes in protein abundances were analysed using label-free quantification. Principle component analysis of differentially expressed proteins identified groupings associated with joint pathology. Findings were validated using ELISA. Lactotransferrin (LTF) abundance was increased in sepsis compared to all other groups and insulin-like growth factor-binding protein 6 (IGFBP6) abundance decreased in sepsis compared to other disease groups. Pathway analysis identified upregulation of the complement system in synovial joint sepsis and the downregulation of eukaryotic translation initiation factors and mTOR signalling pathways in both OA and OC compared to the healthy group. Overall, we have identified a catalogue of proteins which we propose to be involved in osteoarthritis, osteochondrosis and synovial sepsis pathogenesis. SIGNIFICANCE: Osteoarthritis, osteochondrosis and synovial sepsis, which can be life-threatening, are common articular conditions in which rapid and specific diagnosis, monitoring and prognostication remains a challenge for practicing veterinarians. This study has identified that the equine synovial fluid proteome exhibits distinctive profile changes between osteoarthritis, osteochondrosis, synovial sepsis and healthy joints. Elevated synovial abundance of lactotransferrin and decreased insulin-like growth factor-binding protein 6 were both found to distinguish synovial sepsis from all other study groups. Thus, these protein markers may have a future role in clinical practice to enable an earlier and reliable diagnosis of synovial sepsis.