Conventional experimental approaches to understand glaucoma etiology and pathogenesis and, consequently, predict its course of progression have not seen much success due to the involvement of numerous molecular, cellular, and other moieties. An overwhelming number of these moieties at different levels combined with numerous environmental factors further complicate the intricacy. Interaction patterns between these factors are important to understand yet difficult to probe with conservative experimental approaches.We performed a system-level analysis with mathematical modeling by developing and analyzing rate equations with respect to the cellular events in glaucoma pathogenesis. Twenty-two events were enlisted from the literature survey and were analyzed in terms of the sensitivity coefficient of retinal ganglion cells. A separate rate equation was developed for cellular stress also. The results were analyzed with respect to time, and the time course of the events with respect to various cellular moieties was analyzed.Our results suggest that microglia activation is among the earliest events in glaucoma pathogenesis. This modeling method yields a wealth of useful information which may serve as an important guide to better understand glaucoma pathogenesis and design experimental approaches and also identify useful diagnostic/predictive methods and important therapeutic targets.We here report the first mathematical model for glaucoma pathogenesis which provides important insight into the sensitivity coefficient and glia-mediated pathology of glaucoma.Faiq MA, Sidhu T, A Novel Mathematical Model of Glaucoma Pathogenesis. J Curr Glaucoma Pract 2019; 13(1):3-8.