Animal models of glaucoma, a neurodegenerative disease affecting the retina, offer the opportunity to study candidate molecular biomarkers throughout the disease. In this work, the DBA/2J glaucomatous mouse has been used to study the systemic levels of several proteins previously identified as potential biomarkers of glaucoma, along the pre- to post-glaucomatous transition. Serum samples obtained from glaucomatous and control mice at 4, 10, and 14 months, were classified into different experimental groups according to the optic nerve damage at 14 months old. Quantifications of ten serum proteins were carried out by enzyme immunoassays. Changes in the levels of some of these proteins in the transition to glaucomatous stages were identified, highlighting the significative decrease in the concentration of complement C4a protein. Moreover, the five-protein panel consisting of complement C4a, complement factor H, ficolin-3, apolipoprotein A4, and transthyretin predicted the transition to glaucoma in 78% of cases, and to the advanced disease in 89%. Our data, although still preliminary, suggest that disease development in DBA/2J mice is associated with important molecular changes in immune response and complement system proteins and demonstrate the utility of this model in identifying, at systemic level, potential markers for the diagnosis of glaucoma.