Background: The benefits of physical exercise include conferring neuroprotection against the pathophysiological changes associated with neurodegenerative disorders, including retinal degenerations. Although the physical effects of exercise are well understood, the molecular pathways underpinning exercise-induced cellular protection remains unclear. In this work, we aim to profile the transcriptomic changes that occur in the retina during exercise that could contribute to exercise-induced retinal protection. Methods: C57Bl/6J mice were either given free access to open running wheels for a period of 28 days (exercise) or housed under normal conditions (sedentary) and then subjected to 5 days of photo-oxidative damage (PD)-induced retinal degeneration. RNA sequencing and pathway and modular gene co-expression analyses were subsequently performed on retinal lysates of exercised and sedentary mice exposed to PD as well as dim-reared controls. Findings: In response to voluntary exercise without PD, exercised mice appeared to alter their retinal gene profile, modulating pathways that could act as a pre-conditioning response to major stressors. Interestingly, these modulated pathways were dependent on the frequency at which the mice engaged in the act of voluntary exercise. Following 5 days PD, inflammatory and extracellular matrix integrity pathways were significantly modulated, with the gene expression profile of exercised mice more closely trending towards that of a healthy retina. Interpretation: We suggest that frequent engagement in voluntary exercise may mediate retinal protection by influencing key pathways involved in regulating retinal health and shifting the transcriptomic profile to a healthy phenotype.