Background and objectives: Saffron is a known flavor with medicinal properties. Persian and Chinese medicines use saffron to treat several diseases. Saffron has neuroprotective and various other effects. In the present study the combinatory effects of saffron together with intensive light exposure were studied. Methods: Data are derived from Gene Expression Omnibus (GEO) database and assessed via R program. The significant differentially expressed genes (DEGs) including the individuals related to net effect of light exposure, the compensated dysregulated genes by saffron, and the genes associated to the combinatory effects of saffron and light exposure were determined and analyzed via protein-protein interaction (PPI) network analysis and gene ontology to find the affected critical biological processes. Results: Eighty-five genes dysregulated by light exposure in presence and absence of saffron in Sprague Dawley rats RETINA. Saffron protected 20 DEGs from light damage. “Cellular response to retinoic acid” and “lymphocyte chemotaxis” were pointed out as the crucial protected biological processes. A number of 559 DEGs including 20 hub-bottlenecks with combinatory effect of saffron and light were identified. Nitric oxide production, gene silencing by miRNAs, regulation of necrotic cell death and apoptosis appeared as related events to combinatory effects of saffron treatment and light exposure in mice. Conclusion: The positive alteration in nitric oxide, the effects on gene silencing by miRNAs, and alteration in cell death are the affected phenomena in response to combinatory effects of light and saffron in mouse RETINA. These findings open new window about ability of saffron to regulate basic functions in body.